Crosstalk of Microorganisms and Immune Responses in Autoimmune Neuroinflammation: A Focus on Regulatory T Cells

Abstract

Regulatory T cells (Tregs) are the major determinant of peripheral immune tolerance. Many Treg subsets have been described, however thymus-derived and peripherally induced Tregs remain the most important subpopulations. In multiple sclerosis, a prototypical autoimmune disorder of the central nervous system, Treg dysfunction is a pathogenic hallmark. In contrast, induction of Treg proliferation and enhancement of their function are central immune evasion mechanisms of infectious pathogens. In accordance, Treg expansion is compartmentalized to tissues with high viral replication and prolonged in chronic infections. In friend retrovirus infection, Treg expansion is mainly based on excessive interleukin-2 production by infected effector T cells. Moreover, pathogens seem also to enhance Treg functions as shown in human immunodeficiency virus infection, where Tregs express higher levels of effector molecules such as cytotoxic T-lymphocyte-associated protein 4, CD39 and cAMP and show increased suppressive capacity. Thus, insights into the molecular mechanisms by which intracellular pathogens alter Treg functions might aid to find new therapeutic approaches to target central nervous system autoimmunity. In this review, we summarize the current knowledge of the role of pathogens for Treg function in the context of autoimmune neuroinflammation. We discuss the mechanistic implications for future therapies and provide an outlook for new research directions.

1 Introduction

In the context of infections, Tregs mediate beneficial and detrimental effects on short- and long-term disease outcomes. Although many Treg subsets have been described, thymus-derived (tTregs) and peripherally induced Tregs (pTregs) remain the most important subpopulations (1, 2). Tregs are generally found to express CD4 and either or both the high-affinity receptor for interleukin (IL)-2 CD25⁺ as well as the forkhead box protein P3 (Foxp3) (3). Their expression of intracellular and surface markers, such as CD25, glucocorticoid-induced tumor necrosis factor receptor (GITR) and the inhibitory cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) define their phenotype and function (4–6). tTregs emerge with a CD4⁺CD25⁺Foxp3⁺ phenotype directly from the thymus. They are specific for self-antigens requiring continuous antigenic stimulation for their survival and preservation of self-tolerance, the lack of which may lead to autoimmune disorders (7–11). pTregs on the other hand adopt a regulatory function upon expression of Foxp3 and are therefore likely to be specific to an exogenous antigen (3, 12–16). In the context of infection, Tregs can ameliorate excessive immune responses by interaction with and suppression of immune cells. However, Treg expansion and enhanced Treg function are central mechanisms of pathogen-related immune evasion. Yet, the contribution of Tregs to the pathophysiology of pathogen-mediated diseases as well as the underlying molecular mechanisms remain largely elusive.

In the context of therapeutic interventions, it is important to consider the Janus-faced functions of Tregs in infections potentially providing beneficial or detrimental effects (Figure 1). Defining the mechanisms by which intracellular pathogens alter Treg function might pave the way toward new therapeutic approaches not only in the settings of infections, but also in autoimmune neuroinflammation.

Figure 1

With this review, we intend to give a detailed overview of molecular mechanisms underlying altered Treg function in models of acute and chronic infections as well as in autoimmune neuroinflammation with a focus on multiple sclerosis (MS) (Table 1). We investigate the impact of pathogens on immune cell distributions, profiles, and functionality - particularly Treg functions - in the setting of neuroinflammation. We discuss how the complex changes in Tregs lead to altered function and that the underlying mechanisms could contribute to better understand the pathophysiology of neuroinflammatory diseases and their treatments. We further review the interplay of infection with pathogens and autoimmune processes (Figure 2) and, of particular interest, the clinical targets that result from these interactions (Table 2). In addition, we highlight the interplay between commensal bacteria and the function/plasticity of Tregs. In doing so, we particularly consider the implications for the phenotype of autoimmune phenomena. We point out the need for multi-omic approaches (functional analyses, transcriptomics, proteomics, and metabolomics) to illuminate the complex changes in Tregs leading to altered function (Figure 3).

Figure 2

Figure 3

Overall, our review focuses on past, present and future insights into the role of Tregs in the pathophysiology of pathogen-mediated diseases and in autoimmune neuroinflammation. We discuss established and potential therapeutic strategies in MS resulting from this new molecular understanding.

2 Manuscript/Subsections

2.1 Janus-Faced Nature: Duality of Tregs in Pathogen-Mediated Diseases

In the context of pathogen-mediated diseases, Tregs are Janus-faced (Figure 1): On the one hand, they are the major determinant of peripheral immune tolerance not only controlling immune responsiveness to intrinsic antigens and infective pathogens but also modulating immune capacity (9, 11–13). On the other hand, Tregs dampen favorable pathogen-directed adaptive immunity counter acting complete pathogen clearance and giving rise to chronic infections (14, 53, 54). Their phenotype and functions are, among others, dependent on their localization and the tissue type (55–62).

2.1.1 One Janus Face: Beneficial Treg Effects in Infections

Aside from their immunosuppressive capacity forestalling pathology, Tregs have been shown to facilitate appropriate effector mechanisms. Furthermore, Tregs control immunopathology detrimental to the host body arising from excessive effector immune responses.

Tregs utilize diverse immunosuppressive mechanisms depending on their microenvironment: Expression of CD25, the α-chain of IL-2, leads to consumption of IL-2 inhibiting activation and proliferation of conventional T cells (Tconv) (63–65). Interestingly, Chinen et al. showed that IL-2 expression activates signal transducer and activator of transcription (STAT) 5 further boosting the suppressor function of Tregs (66). Suppression of Tconv next to macrophages can also be triggered by cAMP-mediated protein kinase A (PKA) activation. Here, expression of the ectonucleotidase CD39 by Tregs leads to hydrolyzation of ATP followed by further cleavage of AMP to adenosine by CD73 (67–69). Subsequently, activation of the adenosine receptor A2A causes intracellular accumulation of cAMP which in turn stimulates PKA and associated downstream signaling (70–73). Tregs can induce the death of natural killer cells (NK cells) and other effector cells, such as B cells, dendritic cells (DCs), CD4⁺ and CD8⁺ cells, by releasing granzyme resulting in perforin-dependent apoptosis of target cells (74–76). B cells and DCs are regulated by Tregs via CTLA-4 which binds CD80/CD86 and increases the expression of indoleamine 2,3-dioxygenase (IDO) (77–79). Consecutively, binding of CD28 to CD80/CD86 is limited hampering the crosstalk between Tconv and antigen-presenting cells (APCs). Also, accumulation of IDO can lead to starvation of Tconv and cell cycle arrest, amongst others via degradation of the essential amino acid tryptophan (80, 81). Besides that, T cells can suppress T cell receptor (TCR)-induced Ca²⁺, NFAT and NF-κB downstream signaling (77). The co-inhibitory molecule T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) suppresses pro-inflammatory T helper (Th) 1 and Th17 cells, but not Th2 cell responses (82, 83). Tregs can directly induce angiogenesis via vascular endothelial growth factor or target tissue cells (58). Further immunosuppressive effects of Tregs, e.g. on monocytes and macrophages, are mediated via anti-inflammatory cytokines such as IL-10, IL-35 or tumor growth factor β (TGFβ), cytolysis or metabolic disruption (62, 77, 84).

During acute and chronic (retro-) viral infections, Tregs have been shown to promote the in- and efflux of pro-inflammatory cells into lymph nodes (85, 86). Also, they suppress the proliferation and entry of infected cells (87, 88) and contribute to a memory formation via antigen persistence (89). In mice, Treg response is locally defined controlling magnitude and duration of virus-specific cytotoxic T cell responses (90, 91). For example, in human and murine cytomegalovirus, vaccinia virus and influenza virus, CD8⁺ T cell responses are controlled by Tregs by suppression of the immune response to immunodominant epitopes (92, 93). In human immunodeficiency virus (HIV) low Treg frequencies are strongly associated with increased immune activation, accelerated atherosclerosis and other morbidities linked to inflammation (94–103). A negative correlation between the relative amount of Tregs and inflammation has also been observed for hepatitis C virus (HCV) in humans and mice (104, 105). Here, Tregs suppress not only the production of interferon gamma (IFNγ) but also the expansion and activation-induced cell death of HCV-specific T cells resulting in reduced CD4⁺ T cell reactivity and mitigation of T cell-mediated liver disease (105–109).

In bacterial infections, Tregs show a predominant regulatory function controlling and limiting adaptive and innate immune responses as shown in different mouse studies (110): Immunosuppressive functions of Tregs have been already described for helicobacter hepaticus (111, 112), helicobacter pylori (H. pylori) (113–115), listeria monocytogenes (116), pneumocystis carinii (117, 118).

In toxoplasmosis as a prototypical parasitic infection, Treg depleted mice showed 50-60% mortality during acute infection (119).

2.1.2 Other Janus Face: Detrimental Treg Effects in Infections

Immune responses to pathogens can be impaired by an overly strong suppressive effect of Tregs interfering with early protective immunity (84): Tregs can inhibit effector T cell responses thereby promoting chronic inflammation. In turn, lack of complete eradication of pathogens leads to a reservoir function of human and murine Tregs acting as carriers for respective pathogens promoting their expansion in the environment resulting in spread of infections (120–122). Accordingly, pathogen clearance during the disease course correlates with a decrease in the suppressive capacity of Tregs (123). Vice versa, states of chronic inflammation are often characterized in humans by resistance to immune regulation by Tregs (124–126).

In friend retrovirus (FV) (127–130) and herpes simplex virus (HSV) infection in mice (54, 131, 132), Tregs limit CD8⁺ effector T cell proliferation and functions resulting in viral persistence. Treg expansion is mainly based on excessive IL-2 production by murine, FV-infected effector T cells (90, 91, 133, 134). In HIV, human Tregs inhibit effector T cell responses thereby promoting viral chronicity and opportunistic infections acting as a viral reservoir (Figure 1) (100, 135, 136).

In human and murine mycobacterium tuberculosis (Mtb) infection, expansion of Mtb-specific Tregs interferes with priming and migration of T cells to the infected lung resulting in deficient clearance of Mtb (Figure 1) (137–140). Here, Treg numbers inversely correlate with local mycobacteria-specific immunity. Three human studies have shown an increase in T reg numbers in the blood and at sites of infection during active disease (140–142). In human hepatitis B virus (HBV), the expansion of antigen-specific Tregs suggests their contribution to the liver pathology (143–145). Here, the frequency of Tregs correlates with viral load.

In murine fungal infections such as Candida albicans, the absence of Toll-like receptors (TLRs) and Tregs lead to an increase in immunity to candida via secretion of anti-inflammatory cytokines and improved leukocyte recruitment to infection sites (146, 147).

In parasitic infections [e.g., schistosoma in mice (148, 149), leishmania in humans and mice (150–155), plasmodium, and helminths (156, 157)], Tregs are reported to favor parasite expansion and persistence by limiting effector responses, especially of Th1 and Th2 cells, in an IL-10-dependent manner and by suppression of antigen-specific T cell proliferation (36, 158). Nevertheless, while Treg frequency correlated with parasite pathogen load, it also accounted for reduced liver pathology and improved host survival rates. Also, in murine chronic infections of the protozoan parasite Toxoplasma gondii, a nonresolving Th1 myositis occurs where Treg ablation during chronic infection rescues macrophage homeostasis and skeletal muscle fiber regeneration (159).

2.1.3 Treg/Th17 Ratio in Pathogen-Mediated Diseases

In general, the balance between Th17 and Tregs is crucial for the maintenance of immune homeostasis during pathogen-mediated infections (160–162). By presentation of antigens via major histocompatibility complex II molecules on APCs and certain cytokine environments, naïve Th cells are activated and polarized into either peripherally-induced Tregs or Th17 cells to maintain homeostasis. Among APCs, macrophages are known to promote Treg responses, while DCs mainly activate Th17 cell responses (163). In mice, Th17 differentiation is mainly dependent on the cytokines IL-6 and TGFβ which induce the transcription factor retinoic acid-related orphan receptor gamma t (RORγt) in a STAT3-dependent manner (164, 165). In humans, Th17 differentiation mainly depends on IL-23 and IL-1ß (166–168). Th17 cell differentiation is further stimulated by TGFβ, TNF, IL-6, and IL-21. Maintenance and expansion of Th17 cells is regulated by IL-23 (168). Differentiation towards the Treg subset is stimulated via induction of the transcription factor STAT5 by TGFβ and in the absence of IL-6 (169–172). IL-2 and IL-10 also play important roles in the differentiation of Tregs (173). Th17 cells show pro-inflammatory effects during disease progression, which can result in autoimmunity. Tregs on the other hand, serve as immunoregulatory cells and maintain self-tolerance. These opposing effects are also represented on cytokine level: While Th17 cells secrete mainly IL17, IL-21 and IL-22, Tregs produce IL-10, IL-35 and TGFβ (160). Via IL-17 Th17 cells attract other immune cells, such as macrophages and neutrophils resulting in a state of chronic inflammation. In contrast, Tregs regulate differentiation and activity of Th17 and other T cells (8, 174). The Treg/Th17 ratio can contribute to a wide range of immune responses ranging from predominantly regulatory to stimulatory function. Its balance is crucial for immune homeostasis.

In recently infected SARS-CoV-2 patients, the number of Th17 cells was significantly increased compared to healthy controls causing inflammatory responses due to the production of pro-inflammatory cytokines (175, 176). In contrast, Treg numbers were decreased and even further downregulated in the disease course (177–179). Interestingly, the Treg/Th17 cell ratio and expression levels of their related cytokines were significantly higher in deceased patients than during remission (175).

Likewise, in respiratory syncytial virus infection but also in pulmonary infections in general, Tregs and Th17 cells have opposing features determining clinical severity (136, 177, 180, 181): Tregs promote viral clearance by recruiting CD8⁺ cytotoxic T cells to the lungs and limiting inefficient or excessive T cell responses (Th2, CD4⁺ and CD8⁺) (182–186). In addition, they control the innate immune response by neutrophils and NK cells. In contrast, Th17 cells hamper viral clearance by limiting CD8⁺ T cell responses and enhance Th2 immune responses resulting in a more severe clinical picture (187, 188).

In peripheral blood analysis of HBV patients, the Treg/Th17 ratio was decreased with reduced Treg levels and increased Th17 cell numbers (189). The latter correlated with TGFβ and IL-21 levels. Interestingly, here, the Treg/Th17 ratio was the best marker for predicting the stage of HBV-associated liver cirrhosis (190). In HCV patients, Th17 cells were associated with early infection and repair processes leading to liver fibrosis. Here, TGFβ and IL-10 suppressed Th17 cells (191).

For Mtb, the balance between Tregs and Th17 cells regulates encapsulation and control of lung lesions (192). If Tregs become predominant over Th17, Mtb disseminates more easily and recruitment of neutrophils to the infection sites gets delayed (192).

In gastrointestinal infectious diseases, Th17 are predominant in the acute phase producing the cytokines IL-17A, IL-17F and IL-22. In contrast, Treg/Th17 ratio increases in the chronic phase and infection progress because of the suppressive function of Tregs (193).

2.1.4 Impact of Pathogens on Tregs

Several pathogens impact the immune status exploiting the regulatory T cell compartment to enhance their replication and become persistent (95, 194–196). While tTregs are usually specific for self-antigens requiring continuous antigen stimulation for their survival (8–11), pTregs are converted in the periphery and therefore more likely to be influenced by and specific for a microorganism-derived antigen (13, 14). Induction of Treg proliferation and enhancement of Treg function might be central to immune evasion mechanisms of intracellular pathogens (123, 197). In accordance, Treg expansion is compartmentalized to tissues with high viral replication (here Treg frequency often correlates with viral load) and prolonged in chronic infections (19, 25, 90). However, the molecular mechanisms by which intracellular pathogens alter Treg functions as well as the origin of these Tregs remain incompletely understood (for detailed overview see Table 1).

Some pathogens directly contribute to Treg induction. In humans, for example, hepatocytes infected with HCV or gastric epithelial cells infected with H. pylori induce Tregs via TGFβ production (Table 1) (17, 34). Upon infection with plasmodium falciparum there is a burst of IL-2, IL-10 and TGFβ associated with Treg induction and expansion. Here, Tregs were, among others, induced by TLR9 signaling in mice and expressed high levels of Foxp3 suppressing inflammatory processes and immunity-driving mediators of effector T cells (36–39).

Likewise, viral pathogens such as HSV-1, FV and Japanese encephalitis virus enhance Treg expansion (Table 1). In murine HSV-1, the viral binding site herpes virus entry mediator is upregulated (18). For FV infection, there are two possible mechanisms underlying Treg expansion: IL-2-dependent stimulation versus IL-2-independent, tumor necrosis factor (TNF) receptor 2-dependent upregulation (Table 1) (25–27). In both, Japanese encephalitis virus and Mtb, Treg expansion is a result of programmed death-1 ligand 1 (PD-L1) induction (31–33).

Further, pathogens can enhance Treg functions as shown in HIV infection. Here, upon binding of HIV glycoprotein 120 to the CD4 receptor, Tregs express higher levels of effector molecules such as CTLA-4, CD39 and cAMP and show increased suppressive capacity next to prolonged survival rates (Table 1) (19–23). Of note, expression of Foxp3 by patients with a progressive HIV-1 infection seems to be upregulated by individual T cells due to antigen stimulation. Moreover, Foxp3 expression in CD4⁺ T cells was shown to be a marker of HIV infection and potentially even a prognostic marker of HIV progression (24). Also, in the context of COVID-19 disease, an alteration in the expression of Foxp3 could be detected. More precisely, in patients with a severe disease course, a downregulation of Foxp3 could be detected in T cells indicating an impaired Foxp3-mediated feedback on T cell activation as potential mechanisms underlying disease progression (198). Similarly, human T cell lymphotropic virus 1 associated gene products are reported to inhibit Foxp3 gene expression thereby causing Treg dysfunction (Table 1) (28–30).

Interestingly, women infected with Chlamydia trachomatis displayed increased expression levels of Foxp3 in vaginal swab samples following the clearance of infection due to antibiotic treatment (199). In Candida albicans, prolonged Treg survival rates were achieved by TLR2 signaling and IL-10 production (Table 1) (43). Altered Foxp3 expression could also be detected in the context of parasitic infections: During chronic infection with Leishmania of the Viannia subgenus, a decreased Foxp3 expression was detected (200). Recruitment of Tregs to infection sites of Leishmania major was improved by expression of integrin αEβ7 and CC-chemokine receptor 5 (40, 41). Excitingly, infection with helminth parasites mediated by parasite-secreted proteins could also induce de novo T cell Foxp3 expression (201). This, in turn, may be a way through which parasites can evade the host immune response. Regarding H. pylori infection, it is worth noting that increased expression of Foxp3 on Tregs was observed in Tregs isolated from infected children, possibly contributing to an inverse association between H. pylori infection and allergic disease through changes in Treg functionality (35).

2.2 Role of Tregs in Multiple Sclerosis

Immune homeostasis and self-tolerance are regulated by the development, stability and function of Tregs (202). Tregs control immune capacity thereby influencing bystander immune responses such as allergies or autoimmune diseases (11, 14). Tregs prevent the activation and infiltration of T cells into the central nervous system (CNS) and maintain the homeostasis of the immune system (203–205). By suppressing CD8⁺ T effector cell responses, they limit parenchymal damage during CNS inflammation (206).

Tregs can contribute to the pathogenesis of autoimmune diseases by a multi-layered feed-forward loop (Figure 1) (84): Autoantigens and pro-inflammatory cytokines (IL-1β, IL-6 etc.) activate effector Th cells which further aggravate self-tissue damage by the expression of IL-4, IL-6, IL-10, IL-12 and IFNγ (207). Antigens and cytokines from damaged tissue promote the generation of ‘exTreg’ cells adapting Th-like functions which, in turn, stimulate the activation and expansion of autoreactive Th effector cells. These effector Th cell-like functions of ‘exTreg’ cells also directly stimulate pathogenic immune responses in local tissues and promote the pathogenesis of autoimmune diseases by participating in a feed-forward loop (Figure 1). Strikingly, dysfunctional, instable or insufficient Foxp3 expression can also trigger autoimmunity (15, 208–212): Upon loss of Foxp3, Tregs lose their immunosuppressive capacity adapting phenotype and functionality of Th cells (Th1, Th2, Th17), such as production of IFNγ and IL-17 (Figure 1) (213–215).

In contrast, CD4⁺ HLA-G⁺ tTregs cells were shown to ameliorate polyclonal adaptive immune response suppressing graft-versus-host disease in vivo (216). Likewise, Foxp3⁺ Tregs limit muscle destruction by cytotoxic T cells in dermatomyositis, polymyositis and inclusion body myositis (217).

Treg/Th17 imbalance is associated with autoimmune diseases such as MS, myasthenia gravis, psoriasis, inflammatory bowel diseases and rheumatoid arthritis (165, 218–223). Here, Th17 cells are regarded as the main driver of autoimmune inflammation activating other immune cells and secreting pro-inflammatory cytokines (224, 225). A decrease of Tregs in autoimmune and inflammatory diseases is reported to cause disease progression (226). Therapeutic approaches targeting the described Treg/Th17 axis are promising (227) and mainly aim at neutralizing Th17-secreted cytokines, reducing Th17 cell counts, increasing Treg cell levels and regulating transcription factors such as RORγt, STAT3 and Foxp3 (228–231).

2.2.1 Qualitative Treg Alterations in MS

In MS pathogenesis, T cells acquire an autoreactive phenotype against CNS autoantigens followed by migration into the CNS causing inflammatory lesions. Activation of T cells is induced by molecular mimicry in the periphery or by autoreactive T cells in the CNS (232). Control mechanisms that should prevent autoimmunity, such as selection processes during tTreg development or peripheral suppression by Tregs, are often circumvented by autoreactive T cells (233, 234).

Tregs acquire a phenotype and expression profile resembling Th1 cells, thereby contributing to disease progression (235): Lower expression levels of Foxp3, TGF, CTLA-4 and CD39 were accompanied by an increase in IFN secretion in relapsing-remitting MS (RRMS) patients (236–238). Myelin-reactive T cells secreted high levels of IL-17, IFNγ and granulocyte-macrophage colony-stimulating factor compared to healthy controls (239). Next to an upregulation of markers associated with Th1 identity, Tregs expressed higher levels of the migration markers CD103 and CD49d enhancing transmigration of ‘exTregs’ into the CNS (238). High IL-17 levels have also been detected in the cerebrospinal fluid (CSF) of MS patients during relapse as well as in chronic lesions (222, 240), suggesting that both, the upregulation of IL-17 and down-regulation of Treg-mediated immunity, contribute to MS pathogenesis (241, 242).

Likewise, in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, an altered phenotype and impaired suppressive capacity of Tregs have been associated with clinical deterioration (235, 243, 244). Transfer of Th1-like ‘exTregs’ even lead to induction of EAE in naïve recipient mice. Interestingly, Othy et al. (245) showed that Tregs can suppress Th17 cells by inhibition of intracellular Ca²⁺ signaling and their contact to APCs.

Therefore, therapeutic induction of Tregs as well as modulation of Treg/Th17-related pathways could attenuate the inflammatory immune response resulting in mitigation of disease symptoms (246–250). Interestingly, Haas et al. showed that the immunosuppressive effect of Tregs after alemtuzumab treatment of MS patients was mainly due to an altered composition and reactivity of conventional CD4⁺ cells after immunodepletion (251).

2.2.2 Quantitative Treg Alterations in MS

Treg frequency and the Treg/Th17 ratio were negatively correlated with disease severity in MS patients (252, 253). In RRMS patients, reduced Treg numbers were observed. In EAE, Treg plasticity was studied in detail showing an increase of ‘exTreg’ counts during the preclinical phase until disease maximum (212, 254). In line, remission is linked to an increase in Treg numbers representing a recovery of Treg identity (254). Interestingly, clinically isolated syndrome often preceding the diagnosis of MS was associated with alterations of the Treg compartment in peripheral blood (255) Here, patients displayed lower levels of immunosuppressive CD45RA⁺ Foxp3^low Tregs while levels of non-immunosuppressive CD45RA^- Foxp3^low Tregs and Th17-like Tregs increased. These observations suggest that progression to MS might be preceded by changes to the Treg compartment. A recent study investigating the mechanisms driving Treg dysfunction reported an inhibitory effect of circulating exosomes from MS on Tregs (256). This effect is thought to be mediated by let-7i miRNA interacting with insulin like growth factor 1 receptor and TGFβ receptor 1 expressed by CD4⁺ T cells. Thus, miRNA profiles from MS patients might directly inhibit Treg expansion (256).

2.3 The Interplay of Infections and Autoimmunity - Translation in the Setting of Multiple Sclerosis

It is commonly accepted that the interaction of genetic susceptibility and the exposure to certain environmental factors is crucial for the occurrence of autoimmunity. A major environmental factor contributing to the pathogenesis of autoimmune diseases and, more specifically, autoimmune neuroinflammation is pathogen-mediated infection. One of the underlying mechanisms is so-called molecular mimicry. Here, due to structural similarity of pathogen-derived peptides with host molecules, autoreactive B and T cells become cross-activated leading to an immune response directed against self-antigens (257). Likewise, epitope spreading is involved in the interplay of autoimmunity and infections. In this context, a new infection in an ongoing autoimmune disease leads to tissue damage with exposure of further self-antigens (258). APC-mediated presentation of these antigens to autoreactive lymphocytes then accelerates inflammatory processes (258). Furthermore, infections can facilitate inflammatory processes through bystander activation leading to a general immune response with activation of immune cells such as NK cells or macrophages and thus release of pro-inflammatory cytokines (259). This inflammatory milieu induces an antigen-independent activation of primed B and T lymphocytes at the inflammation site and thereby enhances autoimmune damage. Lastly, pathogen-mediated amplification of autoimmune events involves bacterial or viral superantigens leading to an extremely potent activation of polyclonal autoreactive T cells by binding to major histocompatibility complex II (258). These superantigens lead to a massive proliferation of T lymphocytes with excessive cytokine production, especially of IL-2 and IFNγ, resulting in an exacerbation of autoimmune processes (258).

The Treg compartment is needed to control immunopathology throughout life. However, while Tregs are indispensable for immune regulation, exuberant Treg function might prove detrimental for host defense. For example, in Mtb as a model for chronic bacterial infection, Tregs can delay leukocyte migration from lymph nodes to sites of ongoing infection (107, 260). In line, Treg ablation reduces accumulation of Mtb in lungs of infected mice (139). These observations underpin the potential of Tregs to exert detrimental effects in immune-mediated diseases. The continuum of dysfunctional Treg action is shared between infectious conditions, characterized by exuberant immunosuppression, and autoimmune conditions, characterized by promotion of immunogenicity (84). Common to Treg dysfunction is the instability of Foxp3 (213). Foxp3 is pivotal for Treg homeostasis. However, lineage tracing studies revealed that Foxp3 is frequently lost under autoimmune conditions (213). Loss of Foxp3 leads to generation of the so called ‘exTreg’ phenotype characterized by functions shared with effector Th cells, such as secretion of pro-inflammatory cytokines e.g. IFN-γ and IL-17 (84). Moreover, continuous IL-2 signaling is needed to prevent loss of Foxp3 (261). Intriguingly, inflammatory conditions promote loss of Foxp3 and, therefore, contribute to maintaining autoimmune states (212). Inflamed tissue constitutes a complex micro-environment characterized by immune cell infiltration, pro-inflammatory cytokine secretion and increased (self-)antigen presentation. Treg instability might therefore contribute to sustaining inflammatory conditions whereas inflammation promotes loss of Foxp3 and generation of Tregs more closely resembling effector Th cells further contributing to pro-inflammatory stimuli in a feed-forward loop (84). Intriguingly, Tregs from patients who resolved an HCV infection reacted to a virus-encoded peptide with substantial human homology while Tregs from non-infected patients did not (260). Taken together, the pathogenic potential and lineage instability of Tregs make them suspects for mediating autoimmunity following chronic infections.

One of the best studied pathogens involved in MS pathophysiology is Epstein-Barr virus (EBV). Based on epidemiological similarities, an association of EBV infection and MS was suspected early on (262). Further research subsequently not only proved that virtually all MS patients exhibit an EBV infection (263), but also that prior infectious mononucleosis is associated with a 2-3 times higher risk of developing MS (264). Conversely, this risk is significantly reduced for individuals with a negative EBV serology (265). Particularly interesting in this context are data showing that initially seronegative patients experience seroconversion shortly before the onset of MS symptoms (266). Even in pre-symptomatic patients with EBV, a significant increase in anti-EBV antibodies was found over five years before disease onset suggesting involvement of EBV in early disease stages (267). Interestingly, since an association between EBV serology and early conversion of clinically isolated syndrome into clinically definite MS has been demonstrated (268), EBV serology also appears to correlate with disease activity. Consistently, a correlation between anti-EBV nuclear antigen 1 (EBNA-1) titers, disease progression, lesion load, brain atrophy, and the extent of demyelination in MS patients has been demonstrated (269–271). Further support for an involvement of EBV in MS pathophysiology derives from histological studies revealing an accumulation of EBV-infected B- and plasma cells in MS brain meninges, in cortical as well as in white matter lesions (272–274).

Despite this overwhelming evidence, the molecular mechanisms underlying the role of EBV in the immunopathophysiology of MS are still not properly understood. However, a number of hypotheses exist involving discussion of both modulation of peripheral and CNS-localized immune responses. In the periphery, EBV might lead to a cross-activation of pathogenic T cells via molecular mimicry as described above (275). This theory is supported by the fact that EBNA-1-specific T cells react to myelin antigens more frequently than to other auto-antigens causing a release of pro-inflammatory IFNγ (276). Furthermore, EBV-reactive T cells were isolated from the CSF of MS patients also recognizing myelin basic protein (MBP) (277). In addition, a very recent study found cross-reactivity between EBNA-1 and the recently identified MS autoantigen called anoctamin 2 further supporting EBV-induced molecular mimicry (278). Another hypothesis proposes that EBV infection of peripheral B cells induces the expression of aB-crystallin. As it is also expressed in oligodendrocytes, an aB-crystallin-directed T cell response might ultimately lead to demyelination (279). Furthermore, there is evidence for EBV infection of B cells leading to a release of predominantly pro-inflammatory cytokines such as IL-6 or TNFα and simultaneously impeding immunoregulatory processes by reducing IL-10 levels (280, 281). Further evidence derives from recent data providing another pathophysiological link between EBV infections and MS. Wang et al. reported an autoreactive CD4⁺ T cell clone showing cross-reactivity between HLA-DR-derived self-proteins, EBV antigens, as well as autoantigens presented by HLA-DR allomorphs DR2a and DR2b (282). Thus, EBV antigens could be actively involved in the activity of autoreactive CD4⁺ T cells. Since HLA-DR15 is one of the genetic factors most strongly associated with MS, this link highlights the relevance of EBV infection in the pathogenesis of MS (282). A theory with regard to the modulation of peripheral immune processes describes that the invasion of autoreactive T- and EBV-infected B cells into the CNS is forced by expression induction of EBV-induced G protein-coupled receptor 2 thereby fostering the neuroinflammatory response (Figure 2) (275, 283–285).

In the CNS, the accumulation of infected B cells within the meninges and perivascular cuffs suggests that these B cells may elicit a CD8⁺ T cell response, leading to a multiplication of the inflammatory response via bystander activation (272, 286). Expression of superantigens by EBV-infected B cells could further lead to an excessive T cell response (287). Finally, it is hypothesized that EBV-induced immortalization of infected B cells and exhaustion-induced defective elimination lead to an accumulation of EBV-infected autoreactive B cells causing a permanent exposure to CNS antigens (Figure 2) (288–290). This exposure might considerably aggravate CNS damage in the context of autoimmune neuronal inflammation by antigen expression, autoantibody production, as well as by providing survival signals to autoreactive T cells.

Besides EBV, human endogenous retroviruses (HERVs) seem to be significantly involved in MS pathophysiology. These proviruses which account for circa 8% of the genome originate from exogenous infection of primate germ line cells millions of years ago and are today part of the human DNA (291). While they are functionally inactive under physiological conditions, pathological triggers such as viral infections can induce reactivation and thus production of viral proteins (292). First evidence of an involvement in MS dates back more than 30 years when retrovirus transcription was found in the supernatants of meningeal cell cultures of MS patients (293). Different HERVs such as HERV-H, HERV-K and HERV-W were subsequently associated with MS (294, 295). In addition to an increased HERV-W expression in MS patients (296), observations of higher antibody reactivity to certain HERV-W sequences in MS patients (297) and HERV-W upregulation in MS plaques correlating with disease activity support the involvement of HERVs in MS (298). There is also clinical evidence of a relationship of HERVs and MS since patients expressing high levels of HERV-W show a poorer prognosis in early disease stages and increased disease progression (299). Accordingly, HERV-W load also correlates with disease activity and the occurrence of relapses (300). Once more, the possible underlying mechanisms are diverse. For example, reactivation of HERV-W proteins leads to an activation of both innate and adaptive immune responses in MS (301). Thus, dysregulated expression of HERVs may contribute to CNS damage such as observed in a severe combined immunodeficiency mouse model (302). This dysregulated HERV-W activity is likely to involve binding of its envelope protein (ENV) to TLR4 and its co-receptor CD14 which triggers the release of pro-inflammatory cytokines such as TNFα, IL-1β or IL-6 fostering the autoimmune response (303–305). Furthermore, HERV-W-derived proteins such as ENV show cross-reactivity with myelin antigens amplifying the neuroinflammatory response (306). Aside from immune-mediated mechanisms, HERV-W ENV also interferes with remyelination via the inhibition of oligodendrocyte precursor cell (OPC) differentiation (307). Moreover, it also induces a pro-inflammatory activation of myeloid cells which, in turn, contributes to axonal damage and thus neurodegeneration even in long-standing MS cases (308). As there is a monoclonal antibody available that neutralizes HERV-W-induced detrimental effects, endogenous retroviruses constitute an attractive target for future MS therapies (Figure 2) (47, 309).

There is an exciting connection between EBV and HERVs. Exposure of EBV-derived glycoprotein 350 to B cells, monocytes, macrophages, as well as astrocytes leads to a significant increase in the expression of HERV-W and syncytin-1 and is thus also associated with unfavorable processes (310). Similar to EBV, human herpes virus 6 (HHV-6) infection can trigger the expression of HERV-W as well as a HERV-related superantigen (Figure 2) (311, 312). HHV-6 is a neurotropic virus that is divided into two subtypes, of which subtype A can be found in oligodendrocytes of MS white matter lesions (313). In addition to the expression of HHV-6 antigens in MS plaques (314), further evidence for an involvement of HHV-6 in MS pathogenesis derives from elevated anti-HHV-6 antibodies in the CSF of MS patients, especially in patients with an exacerbated disease indicating HHV-6 as a trigger for disease aggravation (315–317). Interestingly, in a non-human primate MS-like animal model, prior infection with HHV-6 resulted in a worse outcome further supporting a detrimental impact of HHV-6 on MS (318). One of the HHV-6-mediated mechanisms contributing to MS pathophysiology involves molecular mimicry since cross-reactivity between HHV-6 and MBP was shown to induce cytotoxic T cell-mediated oligodendrocyte death (319). This idea is further supported by a close sequence homology between MBP and the HHV-6-derived U24 protein (320). Furthermore, it is suggested that HHV-6 binding to the CD46 receptor leads to a T cell-mediated autoimmune reaction (321). Also, increased IL-23 release by DCs and IL-17 production by T cells with a concomitant decreased secretion of the immunoregulatory IL-10 provide potential mechanisms of how also HHV-6 might exacerbate neuroinflammatory processes (Figure 2) (321).

Apart from viral infections, there is also evidence for the involvement of bacterial pathogens in MS pathophysiology. A large meta-analysis, for instance, has shown that MS patients have a significantly higher incidence of Chlamydia pneumoniae (C. pneumoniae) DNA and intrathecally synthesized immunoglobulins in their CSF compared to patients with other neurological diseases (322). In EAE, systemic infection of mice with C. pneumoniae led to dissemination of the pathogen into the CNS accompanied by an aggravation of autoimmune neuroinflammation through reduced Th1 cell proliferation as well as IFNγ production (Figure 2) (323). Nevertheless, the available data is still unclear and controversially discussed.

Whereas the pathogens mentioned so far all have a negative impact on the processes in MS, this is different for H. pylori. In MS cohorts for example, a reduced prevalence of the pathogen compared to controls was demonstrated (324). Even more, MS patients being seropositive for H. pylori showed reduced disability scores (325). In EAE, infection with H. pylori resulted in reduced disease progression, milder proliferation of autoreactive cells, and lower infiltration of pro-inflammatory effector Th1 and Th17 cells into the CNS (Figure 2) (326). A protective role of H. pylori is also assumed in other autoimmune diseases such as asthma (327) or inflammatory bowel disease (328).

Likewise, strong evidence for a protective role in MS disease development has been demonstrated for some parasites. First indications derive from epidemiological investigations, which showed an inverse relationship between parasites like Trichuris trichiura and the occurrence of MS (329). In fact, the prevalence of MS seemed to decrease when the contamination level exceeded 10% (329). Of note, parasite-infected MS patients showed a significantly decreased number of relapses, a minor decline in disability scores, and reduced magnetic resonance imaging (MRI) disease activity compared to patients without helminthic infection (144). Parasitic infections exert an anti-inflammatory effects both on the parasite-specific response and the inflammatory response directed against other antigens in the sense of bystander suppression (330). In mice, helminth infection significantly attenuated both the incidence and clinical symptoms of EAE (331, 332). This amelioration was accompanied by a decrease in pro-inflammatory IFNγ, TNFα, IL-17, and IL-12 with a simultaneous increase in the release of immunoregulatory IL-10 and TGFβ (330–332). Also in humans, helminth infection was associated with induction of CD4⁺CD25⁺Foxp3⁺ T cells suppressing the inflammatory response (333). Beyond Tregs, regulatory B cells secreting IL-10 were detected in greater numbers in helminth-infected individuals suffering from MS (334). Further, the MBP-specific immune response was characterized by a decreased release of pro- next to an enhanced release of anti-inflammatory cytokines in patients with a parasitic infection (Figure 2) (333). Interestingly, the protective effects of helminths infection were shown to be reversed following an anthelmintic treatment concerning both the clinical as well as radiological MS activity and the immunosuppressive effects in terms of the Treg activity (335, 336).

In summary, for many pathogens there is versatile evidence for modulation of autoimmune processes in the context of neuroinflammation in MS. Nevertheless, it has not yet been possible to conclusively define the underlying molecular mechanisms.

2.3.1 Therapeutic Targets

The above findings on detrimental but also beneficial effects of pathogenic infections have led to therapeutic approaches - in some cases despite continuing doubts about the mechanistic background.

In the case of EBV, attempts have been made to prevent an acute EBV infection by prophylactic vaccination thereby reducing the risk for development of MS (274). However, there is currently no appropriate vaccination available. In general, antibodies directed against certain EBV proteins expressed during latency to increase anti-EBV immunity would be a promising strategy. Once again, however, no study results are available to date (274). In contrast, cell-based immunotherapies appear to be a more promising approach. In particular, the application of autologous or allogenic T cells targeting EBV-infected B cells came into focus. A first successful application of this therapy was already demonstrated in a patient suffering from secondary progressive MS (337). Subsequently, a study on the effects of a EBV-specific autologous T cell therapy using in vitro expanded T lymphocytes interfering with EBNA-1 and latent membrane proteins 1 and 2A was initiated (Table 2) (45). Clinical improvement occurred in 7 out of 10 included MS patients. Of note, this was only a safety trial therefore lacking a placebo group. Further studies elucidating the impact of autologous or allogenic T cells attacking EBV-infected B cells are underway (Table 2).

HERV-targeted therapies, on the other hand, have reached a more advanced stage. As already pointed out, HERV and HERV-related proteins such as ENV exert an unfavorable effect on OPCs and myeloid cells and thus on remyelination and neurodegeneration (307–309). In view of the persistent lack of remyelinating therapies (338), it is particularly interesting that this inhibition can be reversed by the anti-HERV-W IgG4 monoclonal antibody GNbAC1 (temelimab) (309). Besides promotion of remyelination, GNbAC1 impedes the release of pro-inflammatory cytokines (339). Application of GNbAC1 led to favorable effects in numerous early-phase studies (46, 340–342). Given these pre-clinical results, two phase IIa and IIb trials were initiated (Table 2) (47). Therapy with 18 mg/kg resulted in a significant reduction of the number of T1-hypointense lesions after 48 hours. Moreover, there was a consistent trend of reduced brain atrophy and a magnetization transfer ratio decrease indicating a positive impact on remyelination. However, GNbAC1 failed to achieve the primary endpoint of the study, i.e. reduction of gadolinium-enhancing lesions (GELs), possibly because of underdosing. However, the beneficial MRI effects on neurodegeneration raised hope and led to the initiation of a new phase II study (Table 2) (47). Another HERV-related approach is based on the theory that antiretroviral therapies can also induce inhibition of HERVs in MS (343). In a baseline-versus-treatment phase IIb study, 20 patients with active RRMS were treated with the integrase inhibitor raltegravir for 3 months (Table 2) (48). However, the primary study endpoint reduction in lesion load or development of new lesions during the treatment period compared with baseline was not met.

Although to date the evidence regarding C. pneumoniae is quite sparse, therapy with rifampicin or azithromycin for 6 months were compared with placebo in newly diagnosed RRMS patients with evidence of C. pneumoniae infection in the CSF (Table 2) (44). The primary endpoint, reduction of GELs, was not reached. Only a decrease in brain atrophy was found under antibiotic therapy. However, given the very small number of subjects, these results should be interpreted with great caution.

Recently, there are also first therapeutic approaches that exploit the protective effects of helminth infection on MS. In a small phase I study, MRI activity in five treatment-naïve RRMS patients was compared between baseline and after probiotic treatment with 2500 Trichuris suis ova every two weeks for three months (Table 2) (49). Under treatment, there was a reduction of new GELs by 70% compared to baseline with a return to baseline after two months of follow-up. The reduction of lesions was also associated with increased serum levels of of IL-4 and IL-10 in 80% of the participants (336). The follow-up study including 16 RRMS patients also showed a trend of reduction of active MRI lesions compared to baseline (344). Furthermore, there was an increase of Tregs observed during this trial. A safety study evaluating the effect of orally administered 2500 Trichuris suis eggs in 10 MS patients could not observe Trichuris suis ova-induced effects on disease progression (Table 2) (51, 336). In line, in this study there were no significant alterations detected regarding cytokine expression and T cell-specific transcriptions factors (336). A 9-month double-blind, randomized, placebo-controlled study enrolling 71 RRMS patients investigated the effect of transcutaneous application of hookworm larvae on lesion burden (Table 2) (50). Of note, treatment with hookworm larvae increased the proportion of Tregs in the peripheral blood. Furthermore, the study showed a tendency of reduced new or enlarging lesions as well as an ameliorated MRI activity in the treatment group. However, these differences were not significant (50). Given these inconsistent results together with methodological limitations such as small sample sizes, further studies are required to sufficiently address the therapeutic potential of helminth infections in MS (336).

2.4 Microbiome - the Missing Link Between Biomolecular Treg Signatures and Clinical Phenotype?

In recent years, the important role of the gut microbiome has been recognized in autoimmune diseases and pathogen-induced immune responses (345, 346). The interplay of the gut microbiome and the immune system may explain its seemingly universal impact on a great variety of diseases including autoimmune diseases, cancer, vascular disease, and even psychiatric disorders (347–350).

Importantly, a variety of factors modulate the composition of the microbiome. Hence, the relationship between the host and the microbiome needs to be understood as a dynamic rather than static process (351). One of the most influential factors of the microbiome is the diet, which under unfavorable conditions induces dysregulation in the form of dysbiosis (351). This dysbiosis, in turn, contributes to an increased incidence of gut-distal autoimmune phenomena such as autoimmune arthritis (352) or type 1 diabetes (353) through alterations in Treg/Th17 balance. In general, the dynamic balance or dysbalance of Tregs and Th17 is suggested to be a main effector mechanism by which the gut microbiome influences systemic immunity (354). Furthermore, antibiotic therapy has an enormous impact on the microbiome and thus on the function of CD4⁺ T cells. For example, antibiotic therapy not only leads to an altered colonic but also tTreg TCR repertoire (355). Likewise, antibiotic-treated mice show a significant reduction of Tregs in the colonic lamina propria (356, 357). Similarly, also germ-free mice exhibited a reduced Treg population (356, 358). However, restoration of the microbiome caused a strong re-expansion of Tregs in these mice (358). Importantly, the effects of an altered microbiome and thus altered Treg/Th17 balance expanded from the local milieu into the whole body. Consistent with this, it has been shown that gut-resident T cells traffic between different organs thereby exerting a systemic effect on the immune system (359, 360). In addition, a reduction of CD4⁺ memory T cells expressing the gut-homing chemokine receptor CC-chemokine 9 was detected in secondary progressive MS patients (361). These gut tropic CC-chemokine 9⁺ memory T cells were shown to exhibit a regulatory phenotype potentially contributing to the conversion of RRMS to secondary progressive MS (361).

Importantly, with respect to microbiome-mediated effects on immunoregulatory mechanisms, tTregs and pTregs need to be distinguished. Unlike tTregs, pTregs exhibit a TCR repertoire directed against microbiota and dietary antigens (362–364). In addition to pTregs and tTregs, other Treg populations such as latency-associated peptide-expressing Tregs, type 1 Tregs, RORγt-expressing Tregs, or GATA binding protein 3⁺ Tregs have been shown to play an essential role in mediating intestinal and extra-intestinal immune homeostasis (365).

This knowledge on the interplay of microbiome, Tregs and autoimmunity provides the rationale to investigate possible microbiome-associated therapeutic strategies such as a modified diet or use of probiotics to change Treg plasticity and function in a favorable way to treat autoimmunity. Therefore, the identification of the involved pathogens and signaling pathways is essential. One of the underlying mechanisms involves intestinal epithelial cell- and microbiota-mediated modulation of DCs leading to an immunoregulatory phenotype through upregulation of IL-10, TGFβ and retinoic acid (365). The potent induction of colonic Tregs by Clostridium species has been well studied. Colonization of germ-free mice with a composition of 46 Clostridium strains resulted in a marked expansion of Tregs (356). Matrix metalloproteinases induced by Clostridium were involved in this expansion and promoted the differentiation and survival of Tregs via TGFβ. Furthermore, Clostridia are known to enhance levels of short-chain fatty acids (SCFAs) (366) which effectively stimulate Tregs. For example, in contrast to long-chain fatty acids that promote a Th1 as well as Th17 response, SCFA administration induces a reduction in the number of Th1 cells but an increased proliferation of gut Tregs (367, 368). Accordingly, application of SCFAs led to a significantly reduced disease progression in EAE and inflammation in ulcerative colitis (367, 369). Protective effects on type 1 diabetes in pre-diabetic mice as well as in a model of collagen-induced arthritis have also been described (368, 370). Interestingly, the SCFAs-induced effects appear to be mediated in part by epigenetic modifications via a suppression of histone deacetylases (371, 372). Despite these protective effects in several models of autoimmune diseases, SCFA application led to disease aggravation in an inflammatory model of rheumatoid arthritis (368). Therefore, a better understanding of the role of SCFAs and other microbiota metabolites is essential in order to exploit these findings therapeutically in clinical practice. In line with a significant impact of dysbiosis in the pathophysiology of MS, a Japanese study observed moderate dysbiosis in the microbiome of RRMS patients compared to healthy controls (373). Primarily, this involved a reduction of clostridial species as well as Bacteroidetes. Interestingly, however, the reduction did not affect the clostridial species, which is commonly known to have a protective effect on autoimmune processes by inducing colonic Tregs. This, in turn, underlines that deeper insights, especially into the influence of distinct species, are essential for translational approaches aiming to modulate the microbiome.

Additionally, several studies have demonstrated the relevance of Bacteroides fragilis, a human symbiont, for the function of Tregs (374, 375). By binding to TLR2, Bacteroides fragilis-derived capsular polysaccharide A as well as outer-membrane vesicles cause an immunosuppressive phenotype in terms of a significant expansion of IL-10-releasing intestinal Tregs (376, 377).

There is also evidence for a role of Akkermansia calcoaceticus and Akkermansia muciniphila in the context of autoimmune neuroinflammation. These bacteria induce impaired Treg conversion in peripheral blood mononuclear cells with concomitant stimulation of Th1 cell differentiation (378). Interestingly, in MS patients, a considerably increased occurrence of Acinetobacter and Akkermansia could be found, which, however, was decreased under MS therapy (351, 378, 379).

Furthermore, there is evidence of a DC-mediated Treg-promoting effect of Lactobacillus, Streptococcus, and Bifidobacterium (380, 381). Regarding potential therapeutic opportunities, application of probiotic mixtures consisting of these bacteria resulted in an expansion of Tregs (382). Therapy with Lactobacilli strains was also able to prevent disease progression in EAE by suppression of autoreactive T cells (383). In addition to these significant pre-clinical results derived from EAE, there is also human data underlining the impact as well as therapeutic potential of probiotic therapeutic approaches: In a small study including 9 MS patients and 13 healthy controls, probiotic therapy with Lactobacillus, Bifidobacterium and Streptococcus over two months led to a modulation of the microbiome as well as of the immune response (384). Thus, this therapy led to an enhancement of immunoregulatory processes with a reduction in the number of inflammatory monocytes as well as the expression of the costimulatory marker CD80 on monocytes. At the same time, probiotic therapy led to a decreased expression of the MS risk alleles HLA.DQA1 and HLA.DPB1 in control patients. However, no significant effects on peripheral Tregs were observed due to the intake of the probiotic treatment. On the microbiome level, several taxa known to be depleted in MS were increased whereas taxa associated with dysbiosis in MS were reduced (384).

Other interesting players influencing the activity and phenotype of bowel tropic Tregs are enteric neurons. Very recent data, for example, show that microbe-responsive Tregs in the colon lamina propria are localized in close proximity to nitrergic and peptidergic nerve fibers (385). Enteric neurons, in turn, prevent differentiation as well as the activity of Tregs in vitro by modulating IL-6. These processes, in turn, are decidedly influenced by microbial signals (385). Recent data describing a vago-vagal liver-brain-gut neuronal arc that induces proliferation and maintenance of pTregs further highlight the relevance of enteric neurons in the context of gut-tropic Tregs (386). Underlying mechanisms involve hepatic vagal sensory afferents that sense the gut microenvironment and on the other hand give input to vagal parasympathetic nerves as well as enteric neurons. Perturbation of the aforementioned afferent neurons led to a reduction in the frequency of pTregs. In vivo, this subsequently led to an increased symptomatology in animal models of colitis (386).

All these considerations have led to therapeutic approaches, such as antigen-based oral immunotherapies, which aim to achieve amelioration of autoimmune diseases via an expansion of Tregs induced by oral antigen administration (365). However, further studies on the critically responsible bacteria of the microbiome as well as the signaling pathways involved are required for a more widespread translational application.

2.5 Tregs in the Advent of the Era of Immunometabolomics

The large variety of pathogens, different transmission routes and complex underlying molecular mechanisms necessitate new comprehensive diagnostic approaches such as immunometabolomics. Several clinical studies addressing autoimmune inflammatory diseases like systemic lupus erythematosus, rheumatoid arthritis, Crohn’s disease and colitis ulcerosa, suggested that disease activity and outcome correlate with immunometabolic signatures (e.g. metabolite levels) (387–389). Moreover, Treg levels were found to be inversely correlated with body weight and body mass index (390). Altered Treg function is not restricted to adipose tissue but can be retrieved in flow cytometry analysis from circulating blood cells pointing to systemic effects (390). Thus, tissue-derived metabolic signals can exert systemic effects via local modulation of function and expansion of Tregs (391). This is particularly true for the adipose tissue. In the visceral adipose tissue of healthy mice, there is a significant enrichment of Tregs, whose deficiency leads to systemic consequences such as metabolic inflammation (60, 60, 392). In obese mice, for example, there is a reduction in the number of Tregs which, in turn, is associated with a decreased lipid content (60). Interestingly, at least in mice, there seems to be an inverse relationship between external lipid accumulation and intrinsic Treg lipid contents. In obese humans, on the other hand, a slight increase in visceral adipose tissue Tregs could be detected (393). Therefore, findings from murine experiments should not be carelessly extrapolated to humans, since underlying mechanisms may vary between species.

Next to the adipose tissue, liver-resident Tregs could also exert systemic effects on metabolic inflammation and systemic metabolism, depending on local metabolism and leading to the development of steatohepatitis or exacerbation of atherosclerosis upon deprivation (394, 395). Furthermore, hyperglycemia in diabetes poses a substantial risk for systemic infections disrupting lymphoid tissue integrity and affecting leukocyte development, phenotype and activity (396). Obesity and type 2 diabetes mellitus drive immune dysfunction, deteriorate infections, and increase sepsis mortality (397). Beyond the direct permissive effects of hyperglycemia on bacterial survival, our knowledge about molecular mechanism of immune deviation in obesity and diabetes remains fragmentary. T cells support coordinated immune responses with their metabolic flexibility (Figure 3) (398–401). Development, activation, function and maintenance of T cells are linked to their metabolic household and, depending on the phase, are associated with an altered metabolic state (399, 402–410).

Basal metabolism of Tregs is characterized by fatty acid oxidation (FAO), metabolism of acetyl CoA, and subsequently tricarboxylic acid cycle activity and oxidative phosphorylation (OXPHOS) (391). In contrast, during the induction of Tregs, there is a switch to a more glycolytic metabolism. This switch is characterized by a displacement of the glycolytic enzyme enolase-1 from the Foxp3 locus allowing the transcription of Foxp3 (411). Inhibition of glycolysis, e.g. using 2-deoxy-D-glucose, results in impeded Treg development due to lack of displacement of enolase-1 and ongoing Foxp3 inhibition (411). In contrast, multiple metabolic pathways are relevant for both homeostasis and proliferation of Tregs. Thus, Tregs show a constitutive activity of mechanistic target of rapamycin (mTOR), which, just like glucose transporter 1, showed an increased expression in proliferating Tregs (412). Interestingly, Procaccini et al. demonstrated that freshly extracted human Tregs show a very high level of glycolysis (413). Furthermore, Li et al. could show that both naturally occurring and tumor-derived Tregs cells exhibit significantly enhanced glucose metabolism as well as increased expression of glycolysis-associated genes further highlighting the role of glycolysis in this state (414). Besides glycolysis, oxidative metabolism has been shown to be critically involved in Treg homeostasis and expansion. Treg proliferation and survival, for instance, influence the function of liver kinase B 1, which, in turn, is an essential inducer of these pathways (415, 416). Further evidence for an involvement of mitochondrial metabolomic pathways derives from a study demonstrating an impaired Treg fitness due to an ablation of the mitochondrial complex III (417). Last, AMP activated protein kinase (AMPK)-dependent FAO is not only crucial for Treg generation, but also for their proliferation (Figure 3) (418–420). While the metabolism of Tregs during homeostasis and proliferation is characterized by a balance of glycolysis and OXPHOS, a predominance of OXPHOS seems to be essential for the suppressive activity of Tregs. Thus, Tregs deficient for proteins that are crucial for mitochondrial metabolism, show significantly reduced suppressive functions and impaired allograft survival (421). Conversely, increased expression of genes that are important to OXPHOS leads to improved Treg suppressive function (421). Further support for a critical role of OXPHOS in the function of Tregs derives from the finding that liver kinase B 1, an enzyme involved in OXPHOS, is essential for the suppressive capacity of Tregs (417). Consequently, deficiency of liver kinase B 1 in mice was associated with a fatal, early-onset autoimmune disease (415). Moreover, also mTOR appears to be involved in the immunoregulatory activity of Tregs via induction of OXPHOS (422). Thus, for example, the suppressive activity of Tregs is associated with increased mTOR signaling. Furthermore, inhibition of mTOR reduced Treg-mediated suppression of T cell proliferation, while deficiency of mTOR in mice triggered autoimmune phenomena (422). In addition, the adequate immunosuppressive function of Tregs may also be associated with both enhanced FAO and fatty acid synthesis (423, 424). For example, stimulation of Tregs leads to increased FAO (418). On the other hand, inhibition of the mevalonate pathway, i.e. fatty acid synthesis, causes a restriction of the suppressive capacity of Tregs (425, 426). In contrast to OXPHOS, FAO, and fatty acid synthesis, enhancement of glycolysis could possibly even induce an impairment of the suppressive capacity of Tregs. For example, Treg-specific deficiency of phosphatase and tensin homolog (PTEN) in mice leads to spontaneous lupus-like disease accompanied by a reduction in the suppressive function of Tregs (427). Of note, increased glycolytic activity was detected in these Tregs, which in turn resulted in insufficient resolution of inflammatory activity EAE and subsequently to augmented disease progression (427). Further evidence for glycolysis-associated insufficiency of immunosuppressive activities derives from Tregs with an enhanced expression of glucose transporter 1, which showed an increased extent of glycolysis but impaired suppression (412). In human Tregs, however, maintenance of glycolytic activity was required for optimal suppressive properties of Tregs further highlighting the need for differential evaluation of immunometabolic processes in human and murine Tregs (411, 428).

In contrast, during migration of Tregs, there appears to be a shift towards glycolytic pathways. For example, hypoxia-inducible factor 1 α (HIF-1α)-deficient Tregs, which exhibit low levels of both glycolysis and enhanced OXPHOS, show increased suppressive properties but impaired migration (429). In mice, this subsequently led to reduced tumor growth and increased survival, likely due to enhanced anti-tumor immunity (429). Consistent with a prominent role of glycolytic processes during migration, stimuli such as CD28 triggering migration of Tregs induced an increased uptake of glucose and markedly enhanced glycolysis (430). Underlying mechanisms involve a PI3K-mTORC2-mediated pathway leading to an enhanced expression of glucokinase. In turn, Tregs deficient for this pathway showed diminished migration but preserved suppressive function. Consistently, Tregs from individuals with a mutation leading to enhanced glucokinase activity showed enhanced migration (430). In summary, a complex interplay and balance of different metabolic pathways underlie the different functional stages of Tregs activity.

Treg dysfunctionality is suggested to be the link between dysmetabolism or dysimmune reactions and pathogens. In fact, hyperglycemia suppressed HIF-1α effects on Tregs in aspergillus fumigatus infection (431). Together with defective NLRP3/IL-1β signal pathway, this led to a more widespread disbalance of Th1/Th2 ratio and Th17 cells (431). The HIF-1α-dependent glycolytic pathway stimulates Th17 differentiation and limits Treg development by promoting the function of RORγt (432, 433).

Targeting immunometabolism as an anti-inflammatory strategy has become an established method in clinical therapies (250, 434, 435). Recently, Palma et al. (436) reported on caloric restriction in mice promoting elimination of Mtb. By means of a multi-omic approach they defined changes in glycolysis next to reduction in fatty acid metabolism and mTOR activity as crucial effects of metabolic reprogramming in this condition (436). In addition to anti-inflammatory therapy, these findings on the metabolic properties of Tregs could also be used in tumor therapy to improve anti-tumor immunity via metabolic interventions. Thus, several aspects of the tumor microenvironment offer an advantage to Tregs, especially in comparison to Th1 or Th17 cells. For example, despite hypoxia, glucose shortness and acidosis, Tregs can compete with other T cells by increased expression of glucose transporters, enhanced glycolytic metabolism, and resistance to lactate-induced acidosis (391).

In the future, omic approaches might enable us to appreciate the complex interplay of immunorelevant pathological conditions and respective Treg functions. To this end, we hypothesize that the metabolic state is capable of reprograming immune responses, with Tregs in a key position, and Treg/Th17 ratio as a valuable judge for T cell function from blood-derived T cell analysis (437). Netea et al. (147) described the chance of so-called ‘innate immune training’: Metabolic shifts can cause epigenetic reprogramming in activated immune cells resulting in an innate immune memory resembling the adaptive immune system.

Strikingly, Arpaia et al. (438) showed that several metabolites produced by commensal bacteria, such as butyrate, short fatty acid and propionate (PA), represent a missing link between microbiota and the immune system promoting generation of pTregs. Interestingly, PA in particular led to a substantial increase in differentiation and proliferation of murine and human Tregs as well as a reduction in the differentiation of Th17 cells (367). Consistently, PA-treated mice showed an ameliorated EAE disease course accompanied by an increase in Treg frequency and IL-10 levels compared to controls. Of note, even application of Tregs derived from mice pre-treated with PA attenuated the clinical symptoms of EAE (367). In addition to these findings obtained from EAE, clinical data from MS patients also pointed in this direction. Not only decreased PA serum and feces levels were found in all disease entities of MS, especially after the first relapse (439). Rather, the add-on administration of PA in MS patients led to a reversal of the Treg/Th17 imbalance, i.e. to an induction of Tregs and a reduction of pro-inflammatory Th1 and Th17 cells. Furthermore, these patients even showed a lower annual relapse rate, a reduced disability progression, and a minor brain atrophy. In line, the microbiome of these patients also showed an upregulation of Treg-inducing genes following PA treatment. These findings indicate a large potential benefit of PA therapy (439).

3 Discussion

In conclusion, microorganisms and immune responses to pathogens are closely interrelated: Programming of the immune system determines the effectiveness of pathogen elimination or their persistence, respectively. Vice versa, pathogens can affect immune responses. Specifically, the balance between T cell subpopulations, in particular the Treg/Th17 ratio, influences the defense against pathogens. In this context, Tregs exhibit a Janus-faced nature: Pronounced Treg activation correlates with a restricted and tissue-protective immune response but can result in pathogen persistence. In contrast, impaired Treg activity, together with Th1 and Th17 responses, can effectively eliminate pathogens but can also result in substantial collateral tissue damage. Consistent with this, mechanisms potentially reprogramming and modulating Treg responses, and their pathogenic conversion are currently intensely investigated. The pathogen itself can impact frequency and function of Tregs by a variety of mechanisms. It can alter immune responses to escape immune activation or even infiltrate immune cells using them as Trojan horses to infect the environment. Metabolic conditions like hyperglycemia or diabetes correlating with high fat diet in animal experiments can reprogram those immune responses by a variety of complex mechanisms not yet fully understood and in urgent need for further investigation. In this context, certain commensal microbiota alter the immune balance, especially the Treg/Th17 ratio.

There is substantial evidence that the interplay of pathogenic infections and immune processes are crucial in the pathogenesis of autoimmune disorders. Several pathogens were shown to be critically involved in MS immunopathophysiology by modulating the immune response. The best evidence is available for host-detrimental effects of EBV and HERVs which seem to fuel neuroinflammation. These effects are induced by different mechanisms such as bystander activation, molecular mimicry, superantigen-induced promotion of the T cell response, and epitope spreading. However, apart from these deleterious effects, protective effects have been demonstrated for numerous parasites, especially helminths, and also H. pylori. Such insights into the interplay of infection and MS have subsequently led to numerous translational approaches aimed at inhibiting deleterious and promoting favorable interactions. In addition to cell-based immunotherapies targeting EBV-infected B cells, the application of the monoclonal antibody GNbAC1 inhibiting HERV-W ENV seems particularly promising. Interestingly, GNbAC1 not only leads to a suppression of pro-inflammatory signaling pathways but also to possible critically desired neuroregenerative effects. The underlying mechanisms probably include improved OPC differentiation and a neutralization of pro-inflammatory myeloid cells. Accordingly, results of the ongoing phase IIb ProTect-MS study are awaited with great interest.

Further therapeutic opportunities might be provided by a closer understanding of the interaction of the intestinal microbiome with Tregs thereby influencing the Treg/Th17 balance. Dysregulation of this balance or of the microbiome in the sense of dysbiosis promotes the occurrence of autoimmune diseases. Furthermore, the composition of the microbiome seems to have enormous effects on the phenotype of Tregs. However, these effects are not only local, but lead to a systemic modulation of the immune response with both potentially unfavorable and favorable consequences. Nevertheless, deeper insights into this interplay are necessary to develop therapeutic strategies to take advantage of this knowledge. Possible candidates for this are Clostridium species or Bacteroides fragilis, which provide favorable immune modulatory properties with regard to autoimmunity by promoting regulatory capacities of Tregs.

Impacting both innate and adaptive immune responses, future research should identify the most relevant pathogen species as well as define molecular mechanisms and substrates underlying reprogramming of the immune balance. Such new insights could be used to therapeutically induce or modify Tregs to treat autoimmune diseases and immune responses in general. Hence, multi-omic approaches may unravel the interplay between microorganism-modulated Treg function and autoimmune neuroinflammation. Understanding the underlying molecular mechanisms could further contribute to the development of targeted therapies.

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References

• 1

  ThorntonAMLuJKortyPEKimYCMartensCSunPDet al. Helios+ and Helios- Treg Subpopulations Are Phenotypically and Functionally Distinct and Express Dissimilar TCR Repertoires. Eur J Immunol (2019) 49:398–412. doi: 10.1002/eji.201847935

  • CrossRef
  • Google Scholar

• 2

  AbbasAKBenoistCBluestoneJACampbellDJGhoshSHoriSet al. Regulatory T Cells: Recommendations to Simplify the Nomenclature. Nat Immunol (2013) 14:307–8. doi: 10.1038/ni.2554

  • CrossRef
  • Google Scholar

• 3

  GavinMARasmussenJPFontenotJDVastaVManganielloVCBeavoJAet al. Foxp3-Dependent Programme of Regulatory T-Cell Differentiation. Nature (2007) 445:771–5. doi: 10.1038/nature05543

  • CrossRef
  • Google Scholar

• 4

  RudenskyAY. Regulatory T Cells and Foxp3. Immunol Rev (2011) 241:260–8. doi: 10.1111/j.1600-065X.2011.01018.x

  • CrossRef
  • Google Scholar

• 5

  ToneMToneYAdamsEYatesSFFrewinMRCobboldSPet al. Mouse Glucocorticoid-Induced Tumor Necrosis Factor Receptor Ligand Is Costimulatory for T Cells. Proc Natl Acad Sci USA (2003) 100:15059–64. doi: 10.1073/pnas.2334901100

  • CrossRef
  • Google Scholar

• 6

  TakahashiTTagamiTYamazakiSUedeTShimizuJSakaguchiNet al. Immunologic Self-Tolerance Maintained by CD25(+)CD4(+) Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte-Associated Antigen 4. J Exp Med (2000) 192:303–10. doi: 10.1084/jem.192.2.303

  • CrossRef
  • Google Scholar

• 7

  RubtsovYPNiecREJosefowiczSLiLDarceJMathisDet al. Stability of the Regulatory T Cell Lineage In Vivo. Science (2010) 329:1667–71. doi: 10.1126/science.1191996

  • CrossRef
  • Google Scholar

• 8

  SakaguchiSSakaguchiNAsanoMItohMTodaM. Immunologic Self-Tolerance Maintained by Activated T Cells Expressing IL-2 Receptor Alpha-Chains (CD25). Breakdown of a Single Mechanism of Self-Tolerance Causes Various Autoimmune Diseases. J Immunol (1995) 155:1151–64.

  • Google Scholar

• 9

  LevineAGArveyAJinWRudenskyAY. Continuous Requirement for the TCR in Regulatory T Cell Function. Nat Immunol (2014) 15:1070–8. doi: 10.1038/ni.3004

  • CrossRef
  • Google Scholar

• 10

  VahlJCDreesCHegerKHeinkSFischerJCNedjicJet al. Continuous T Cell Receptor Signals Maintain a Functional Regulatory T Cell Pool. Immunity (2014) 41:722–36. doi: 10.1016/j.immuni.2014.10.012

  • CrossRef
  • Google Scholar

• 11

  LegouxFPLimJ-BCauleyAWDikiySErteltJMarianiTJet al. CD4+ T Cell Tolerance to Tissue-Restricted Self Antigens Is Mediated by Antigen-Specific Regulatory T Cells Rather Than Deletion. Immunity (2015) 43:896–908. doi: 10.1016/j.immuni.2015.10.011

  • CrossRef
  • Google Scholar

• 12

  BluestoneJAAbbasAK. Natural Versus Adaptive Regulatory T Cells. Nat Rev Immunol (2003) 3:253–7. doi: 10.1038/nri1032

  • CrossRef
  • Google Scholar

• 13

  MaizelsRMSmithKA. Regulatory T Cells in Infection. In: Advances in Immunology.Elsevier. (2011) 112:73–136. doi: 10.1016/B978-0-12-387827-4.00003-6

  • CrossRef
  • Google Scholar

• 14

  Arce-SillasAÁlvarez-LuquínDDTamaya-DomínguezBGomez-FuentesSTrejo-GarcíaAMelo-SalasMet al. Regulatory T Cells: Molecular Actions on Effector Cells in Immune Regulation. J Immunol Res (2016) 2016:1720827. doi: 10.1155/2016/1720827

  • CrossRef
  • Google Scholar

• 15

  FontenotJDGavinMARudenskyAY. Foxp3 Programs the Development and Function of CD4+CD25+ Regulatory T Cells. Nat Immunol (2003) 4:330–6. doi: 10.1038/ni904

  • CrossRef
  • Google Scholar

• 16

  WilliamsLMRudenskyAY. Maintenance of the Foxp3-Dependent Developmental Program in Mature Regulatory T Cells Requires Continued Expression of Foxp3. Nat Immunol (2007) 8:277–84. doi: 10.1038/ni1437

  • CrossRef
  • Google Scholar

• 17

  HallCHTKasselRTackeRSHahnYS. HCV+ Hepatocytes Induce Human Regulatory CD4+ T Cells Through the Production of TGF-Beta. PloS One (2010) 5:e12154. doi: 10.1371/journal.pone.0012154

  • CrossRef
  • Google Scholar

• 18

  SharmaSRajasagiNKVeiga-PargaTRouseBT. Herpes Virus Entry Mediator (HVEM) Modulates Proliferation and Activation of Regulatory T Cells Following HSV-1 Infection. Microbes Infect (2014) 16:648–60. doi: 10.1016/j.micinf.2014.06.005

  • CrossRef
  • Google Scholar

• 19

  Schulze Zur WieschJThomssenAHartjenPTóthILehmannCMeyer-OlsonDet al. Comprehensive Analysis of Frequency and Phenotype of T Regulatory Cells in HIV Infection: CD39 Expression of FoxP3+ T Regulatory Cells Correlates With Progressive Disease. J Virol (2011) 85:1287–97. doi: 10.1128/JVI.01758-10

  • CrossRef
  • Google Scholar

• 20

  NikolovaMCarriereMJenabianM-ALimouSYounasMKökAet al. CD39/adenosine Pathway Is Involved in AIDS Progression. PloS Pathog (2011) 7:e1002110. doi: 10.1371/journal.ppat.1002110

  • CrossRef
  • Google Scholar

• 21

  BeckerCTaubeCBoppTBeckerCMichelKKubachJet al. Protection From Graft-Versus-Host Disease by HIV-1 Envelope Protein Gp120-Mediated Activation of Human CD4+CD25+ Regulatory T Cells. Blood (2009) 114:1263–9. doi: 10.1182/blood-2009-02-206730

  • CrossRef
  • Google Scholar

• 22

  JiJCloydMW. HIV-1 Binding to CD4 on CD4+CD25+ Regulatory T Cells Enhances Their Suppressive Function and Induces Them to Home to, and Accumulate in, Peripheral and Mucosal Lymphoid Tissues: An Additional Mechanism of Immunosuppression. Int Immunol (2009) 21:283–94. doi: 10.1093/intimm/dxn146

  • CrossRef
  • Google Scholar

• 23

  NilssonJBoassoAVelillaPAZhangRVaccariMFranchiniGet al. HIV-1-Driven Regulatory T-Cell Accumulation in Lymphoid Tissues Is Associated With Disease Progression in HIV/AIDS. Blood (2006) 108:3808–17. doi: 10.1182/blood-2006-05-021576

  • CrossRef
  • Google Scholar

• 24

  SuchardMSMayneEGreenVAShalekoffSDonningerSLStevensWSet al. FOXP3 Expression Is Upregulated in CD4T Cells in Progressive HIV-1 Infection and Is a Marker of Disease Severity. PloS One (2010) 5:e11762. doi: 10.1371/journal.pone.0011762

  • CrossRef
  • Google Scholar

• 25

  JoedickeJJDietzeKKZelinskyyGDittmerU. The Phenotype and Activation Status of Regulatory T Cells During Friend Retrovirus Infection. Virol Sin (2014) 29:48–60. doi: 10.1007/s12250-014-3396-z

  • CrossRef
  • Google Scholar

• 26

  MooreTCGonzagaLMMatherJMMesserRJHasenkrugKJ. B Cell Requirement for Robust Regulatory T Cell Responses to Friend Retrovirus Infection. mBio (2017) 8:e01122–17. doi: 10.1128/mBio.01122-17

  • CrossRef
  • Google Scholar

• 27

  MyersLJoedickeJJCarmodyABMesserRJKassiotisGDudleyJPet al. IL-2-Independent and TNF-α-Dependent Expansion of Vβ5+ Natural Regulatory T Cells During Retrovirus Infection. J Immunol (2013) 190:5485–95. doi: 10.4049/jimmunol.1202951

  • CrossRef
  • Google Scholar

• 28

  YamanoYTakenouchiNLiH-CTomaruUYaoKGrantCWet al. Virus-Induced Dysfunction of CD4+CD25+ T Cells in Patients With HTLV-I-Associated Neuroimmunological Disease. J Clin Invest (2005) 115:1361–8. doi: 10.1172/JCI23913

  • CrossRef
  • Google Scholar

• 29

  WalshPTBenoitBMWysockaMDaltonNMTurkaLARookAH. A Role for Regulatory T Cells in Cutaneous T-Cell Lymphoma; Induction of a CD4 + CD25 + Foxp3+ T-Cell Phenotype Associated With HTLV-1 Infection. J Invest Dermatol (2006) 126:690–2. doi: 10.1038/sj.jid.5700121

  • CrossRef
  • Google Scholar

• 30

  OhUGrantCGriffithCFugoKTakenouchiNJacobsonS. Reduced Foxp3 Protein Expression Is Associated With Inflammatory Disease During Human T Lymphotropic Virus Type 1 Infection. J Infect Dis (2006) 193:1557–66. doi: 10.1086/503874

  • CrossRef
  • Google Scholar

• 31

  GuptaNHegdePLecerfMNainMKaurMKaliaMet al. Japanese Encephalitis Virus Expands Regulatory T Cells by Increasing the Expression of PD-L1 on Dendritic Cells: Immunity to Infection. Eur J Immunol (2014) 44:1363–74. doi: 10.1002/eji.201343701

  • CrossRef
  • Google Scholar

• 32

  PeriasamySDhimanRBarnesPFPaidipallyPTvinnereimABandaruAet al. Programmed Death 1 and Cytokine Inducible SH2-Containing Protein Dependent Expansion of Regulatory T Cells Upon Stimulation With Mycobacterium Tuberculosis. J Infect Dis (2011) 203:1256–63. doi: 10.1093/infdis/jir011

  • CrossRef
  • Google Scholar

• 33

  TrinathJMaddurMSKaveriSVBalajiKNBayryJ. Mycobacterium Tuberculosis Promotes Regulatory T-Cell Expansion via Induction of Programmed Death-1 Ligand 1 (PD-L1, CD274) on Dendritic Cells. J Infect Dis (2012) 205:694–6. doi: 10.1093/infdis/jir820

  • CrossRef
  • Google Scholar

• 34

  BeswickEJPinchukIVEarleyRBSchmittDAReyesVE. Role of Gastric Epithelial Cell-Derived Transforming Growth Factor Beta in Reduced CD4+ T Cell Proliferation and Development of Regulatory T Cells During Helicobacter Pylori Infection. Infect Immun (2011) 79:2737–45. doi: 10.1128/IAI.01146-10

  • CrossRef
  • Google Scholar

• 35

  LeónMAPalmaCHernándezCSandovalMCofreCPerez-MatelunaGet al. Helicobacter Pylori Pediatric Infection Changes FcϵRI Expression in Dendritic Cells and Treg Profile In Vivo and In Vitro. Microbes Infect (2019) 21:449–55. doi: 10.1016/j.micinf.2019.05.001

  • CrossRef
  • Google Scholar

• 36

  BelkaidYBlankRBSuffiaI. Natural Regulatory T Cells and Parasites: A Common Quest for Host Homeostasis. Immunol Rev (2006) 212:287–300. doi: 10.1111/j.0105-2896.2006.00409.x

  • CrossRef
  • Google Scholar

• 37

  HisaedaHTetsutaniKImaiTMoriyaCTuLHamanoSet al. Malaria Parasites Require TLR9 Signaling for Immune Evasion by Activating Regulatory T Cells. J Immunol (2008) 180:2496–503. doi: 10.4049/jimmunol.180.4.2496

  • CrossRef
  • Google Scholar

• 38

  HisaedaHMaekawaYIwakawaDOkadaHHimenoKKishiharaKet al. Escape of Malaria Parasites From Host Immunity Requires CD4+ CD25+ Regulatory T Cells. Nat Med (2004) 10:29–30. doi: 10.1038/nm975

  • CrossRef
  • Google Scholar

• 39

  ScholzenAMittagDRogersonSJCookeBMPlebanskiM. Plasmodium Falciparum-Mediated Induction of Human CD25Foxp3 CD4 T Cells Is Independent of Direct TCR Stimulation and Requires IL-2, IL-10 and TGFbeta. PloS Pathog (2009) 5:e1000543. doi: 10.1371/journal.ppat.1000543

  • CrossRef
  • Google Scholar

• 40

  SuffiaIRecklingSKSalayGBelkaidY. A Role for CD103 in the Retention of CD4+CD25+ Treg and Control of Leishmania Major Infection. J Immunol (2005) 174:5444–55. doi: 10.4049/jimmunol.174.9.5444

  • CrossRef
  • Google Scholar

• 41

  YurchenkoETrittMHayVShevachEMBelkaidYPiccirilloCA. CCR5-Dependent Homing of Naturally Occurring CD4+ Regulatory T Cells to Sites of Leishmania Major Infection Favors Pathogen Persistence. J Exp Med (2006) 203:2451–60. doi: 10.1084/jem.20060956

  • CrossRef
  • Google Scholar

• 42

  CostaFRCMotaCMSantiagoFMSilvaMVFerreiraMDFonsecaDMet al. GITR Activation Positively Regulates Immune Responses Against Toxoplasma Gondii. PloS One (2016) 11:e0152622. doi: 10.1371/journal.pone.0152622

  • CrossRef
  • Google Scholar

• 43

  NeteaMGSutmullerRHermannCvan der GraafCAAvan der MeerJWMvan KriekenJHet al. Toll-Like Receptor 2 Suppresses Immunity Against Candida Albicans Through Induction of IL-10 and Regulatory T Cells. J Immunol (2004) 172:3712–8. doi: 10.4049/jimmunol.172.6.3712

  • CrossRef
  • Google Scholar

• 44

  SriramSYaoSYStrattonCMosesHNarayanaPAWolinskyJS. Pilot Study to Examine the Effect of Antibiotic Therapy on MRI Outcomes in RRMS. J Neurol Sci (2005) 234:87–91. doi: 10.1016/j.jns.2005.03.042

  • CrossRef
  • Google Scholar

• 45

  PenderMPCsurhesPASmithCDouglasNLNellerMAMatthewsKKet al. Epstein-Barr Virus-Specific T Cell Therapy for Progressive Multiple Sclerosis. JCI Insight (2018) 3:124714. doi: 10.1172/jci.insight.124714

  • CrossRef
  • Google Scholar

• 46

  DerfussTCurtinFGuebelinCBridelCRasenackMMattheyAet al. A Phase IIa Randomised Clinical Study of GNbAC1, a Humanised Monoclonal Antibody Against the Envelope Protein of Multiple Sclerosis-Associated Endogenous Retrovirus in Multiple Sclerosis Patients. Mult Scler (2015) 21:885–93. doi: 10.1177/1352458514554052

  • CrossRef
  • Google Scholar

• 47

  HartungH-PDerfussTCreeBASormaniMPSelmajKStuttersJet al. Efficacy and Safety of Temelimab in Multiple Sclerosis: Results of a Randomized Phase 2b and Extension Study. Mult Scler (2021) 13524585211024996. doi: 10.1177/13524585211024997

  • CrossRef
  • Google Scholar

• 48

  GoldJMartaMMeierUCChristensenTMillerDAltmannDet al. A Phase II Baseline Versus Treatment Study to Determine the Efficacy of Raltegravir (Isentress) in Preventing Progression of Relapsing Remitting Multiple Sclerosis as Determined by Gadolinium-Enhanced MRI: The INSPIRE Study. Mult Scler Relat Disord (2018) 24:123–8. doi: 10.1016/j.msard.2018.06.002

  • CrossRef
  • Google Scholar

• 49

  FlemingJOIsaakALeeJELuzzioCCCarrithersMDCookTDet al. Probiotic Helminth Administration in Relapsing-Remitting Multiple Sclerosis: A Phase 1 Study. Mult Scler (2011) 17:743–54. doi: 10.1177/1352458511398054

  • CrossRef
  • Google Scholar

• 50

  TanasescuRTenchCRConstantinescuCSTelfordGSinghSFrakichNet al. Hookworm Treatment for Relapsing Multiple Sclerosis: A Randomized Double-Blinded Placebo-Controlled Trial. JAMA Neurol (2020) 77:1089–98. doi: 10.1001/jamaneurol.2020.1118

  • CrossRef
  • Google Scholar

• 51

  VoldsgaardABagerPGardeEÅkesonPLeffersAMMadsenCGet al. Trichuris Suis Ova Therapy in Relapsing Multiple Sclerosis Is Safe But Without Signals of Beneficial Effect. Mult Scler (2015) 21:1723–9. doi: 10.1177/1352458514568173

  • CrossRef
  • Google Scholar

• 52

  YordanovaIAEbnerFSchulzARSteinfelderSRoscheBBolzeAet al. The Worm-Specific Immune Response in Multiple Sclerosis Patients Receiving Controlled Trichuris Suis Ova Immunotherapy. Life (Basel) (2021) 11:101. doi: 10.3390/life11020101

  • CrossRef
  • Google Scholar

• 53

  KimJMRasmussenJPRudenskyAY. Regulatory T Cells Prevent Catastrophic Autoimmunity Throughout the Lifespan of Mice. Nat Immunol (2007) 8:191–7. doi: 10.1038/ni1428

  • CrossRef
  • Google Scholar

• 54

  BelkaidYTarbellK. Regulatory T Cells in the Control of Host-Microorganism Interactions (*). Annu Rev Immunol (2009) 27:551–89. doi: 10.1146/annurev.immunol.021908.132723

  • CrossRef
  • Google Scholar

• 55

  XiaMHuSFuYJinWYiQMatsuiYet al. CCR10 Regulates Balanced Maintenance and Function of Resident Regulatory and Effector T Cells to Promote Immune Homeostasis in the Skin. J Allergy Clin Immunol (2014) 134:634–44.e10. doi: 10.1016/j.jaci.2014.03.010

  • CrossRef
  • Google Scholar

• 56

  FeuererMHerreroLCipollettaDNaazAWongJNayerAet al. Lean, But Not Obese, Fat Is Enriched for a Unique Population of Regulatory T Cells That Affect Metabolic Parameters. Nat Med (2009) 15:930–9. doi: 10.1038/nm.2002

  • CrossRef
  • Google Scholar

• 57

  BurzynDBenoistCMathisD. Regulatory T Cells in Nonlymphoid Tissues. Nat Immunol (2013) 14:1007–13. doi: 10.1038/ni.2683

  • CrossRef
  • Google Scholar

• 58

  FacciabeneAPengXHagemannISBalintKBarchettiAWangL-Pet al. Tumour Hypoxia Promotes Tolerance and Angiogenesis via CCL28 and Treg Cells. Nature (2011) 475:226–30. doi: 10.1038/nature10169

  • CrossRef
  • Google Scholar

• 59

  TanWZhangWStrasnerAGrivennikovSChengJQHoffmanRMet al. Tumour-Infiltrating Regulatory T Cells Stimulate Mammary Cancer Metastasis Through RANKL–RANK Signalling. Nature (2011) 470:548–53. doi: 10.1038/nature09707

  • CrossRef
  • Google Scholar

• 60

  CipollettaDFeuererMLiAKameiNLeeJShoelsonSEet al. PPAR-γ Is a Major Driver of the Accumulation and Phenotype of Adipose Tissue Treg Cells. Nature (2012) 486:549–53. doi: 10.1038/nature11132

  • CrossRef
  • Google Scholar

• 61

  SharmaARudraD. Emerging Functions of Regulatory T Cells in Tissue Homeostasis. Front Immunol (2018) 9:883. doi: 10.3389/fimmu.2018.00883

  • CrossRef
  • Google Scholar

• 62

  LeiHSchmidt-BleekKDieneltAReinkePVolkH-D. Regulatory T Cell-Mediated Anti-Inflammatory Effects Promote Successful Tissue Repair in Both Indirect and Direct Manners. Front Pharmacol (2015) 6:184. doi: 10.3389/fphar.2015.00184

  • CrossRef
  • Google Scholar

• 63

  GhelaniABatesDConnerKWuM-ZLuJHuY-Let al. Defining the Threshold IL-2 Signal Required for Induction of Selective Treg Cell Responses Using Engineered IL-2 Muteins. Front Immunol (2020) 11:1106. doi: 10.3389/fimmu.2020.01106

  • CrossRef
  • Google Scholar

• 64

  de la RosaMRutzSDorningerHScheffoldA. Interleukin-2 Is Essential for CD4+CD25+ Regulatory T Cell Function. Eur J Immunol (2004) 34:2480–8. doi: 10.1002/eji.200425274

  • CrossRef
  • Google Scholar

• 65

  Baecher-AllanCBrownJAFreemanGJHaflerDA. CD4 ⁺ CD25 ^High Regulatory Cells in Human Peripheral Blood. J Immunol (2001) 167:1245–53. doi: 10.4049/jimmunol.167.3.1245

  • CrossRef
  • Google Scholar

• 66

  ChinenTKannanAKLevineAGFanXKleinUZhengYet al. An Essential Role for the IL-2 Receptor in Treg Cell Function. Nat Immunol (2016) 17:1322–33. doi: 10.1038/ni.3540

  • CrossRef
  • Google Scholar

• 67

  ZhangHYYanKXHuangQMaYFangXHanL. Target Tissue Ectoenzyme CD39/CD73-Expressing Foxp3 ⁺ Regulatory T Cells in Patients With Psoriasis. Clin Exp Dermatol (2015) 40:182–91. doi: 10.1111/ced.12497

  • CrossRef
  • Google Scholar

• 68

  SchulerPJSazeZHongC-SMullerLGillespieDGChengDet al. Human CD4 ⁺ CD39 ⁺ Regulatory T Cells Produce Adenosine Upon Co-Expression of Surface CD73 or Contact With CD73 ⁺ Exosomes or CD73 ⁺ Cells: CD73 Co-Expression in Human CD39 ⁺ T _Reg. Clin Exp Immunol (2014) 177:531–43. doi: 10.1111/cei.12354

  • CrossRef
  • Google Scholar

• 69

  BoppTBeckerCKleinMKlein-HeßlingSPalmetshoferASerflingEet al. Cyclic Adenosine Monophosphate Is a Key Component of Regulatory T Cell–Mediated Suppression. J Exp Med (2007) 204:1303–10. doi: 10.1084/jem.20062129

  • CrossRef
  • Google Scholar

• 70

  DeaglioSDwyerKMGaoWFriedmanDUshevaAEratAet al. Adenosine Generation Catalyzed by CD39 and CD73 Expressed on Regulatory T Cells Mediates Immune Suppression. J Exp Med (2007) 204:1257–65. doi: 10.1084/jem.20062512

  • CrossRef
  • Google Scholar

• 71

  RuedaCMJacksonCMChougnetCA. Regulatory T-Cell-Mediated Suppression of Conventional T-Cells and Dendritic Cells by Different cAMP Intracellular Pathways. Front Immunol (2016) 7:216. doi: 10.3389/fimmu.2016.00216

  • CrossRef
  • Google Scholar

• 72

  KleinMBoppT. Cyclic AMP Represents a Crucial Component of Treg Cell-Mediated Immune Regulation. Front Immunol (2016) 7:315. doi: 10.3389/fimmu.2016.00315

  • CrossRef
  • Google Scholar

• 73

  SuWChenXZhuWYuJLiWLiYet al. The cAMP–Adenosine Feedback Loop Maintains the Suppressive Function of Regulatory T Cells. J Immunol (2019) 203:1436–46. doi: 10.4049/jimmunol.1801306

  • CrossRef
  • Google Scholar

• 74

  CaoXCaiSFFehnigerTASongJCollinsLIPiwnica-WormsDRet al. Granzyme B and Perforin Are Important for Regulatory T Cell-Mediated Suppression of Tumor Clearance. Immunity (2007) 27:635–46. doi: 10.1016/j.immuni.2007.08.014

  • CrossRef
  • Google Scholar

• 75

  GrossmanWJVerbskyJWBarchetWColonnaMAtkinsonJPLeyTJ. Human T Regulatory Cells Can Use the Perforin Pathway to Cause Autologous Target Cell Death. Immunity (2004) 21:589–601. doi: 10.1016/j.immuni.2004.09.002

  • CrossRef
  • Google Scholar

• 76

  GondekDCDeVriesVNowakECLuL-FBennettKAScottZAet al. Transplantation Survival Is Maintained by Granzyme B ⁺ Regulatory Cells and Adaptive Regulatory T Cells. J Immunol (2008) 181:4752–60. doi: 10.4049/jimmunol.181.7.4752

  • CrossRef
  • Google Scholar

• 77

  SchmidtAOberleNKrammerPH. Molecular Mechanisms of Treg-Mediated T Cell Suppression. Front Immun (2012) 3:51. doi: 10.3389/fimmu.2012.00051

  • CrossRef
  • Google Scholar

• 78

  OderupCCederbomLMakowskaACilioCMIvarsF. Cytotoxic T Lymphocyte Antigen-4-Dependent Down-Modulation of Costimulatory Molecules on Dendritic Cells in CD4+ CD25+ Regulatory T-Cell-Mediated Suppression. Immunology (2006) 118:240–9. doi: 10.1111/j.1365-2567.2006.02362.x

  • CrossRef
  • Google Scholar

• 79

  LippensCDuraesFVDubrotJBrighouseDLacroixMIrlaMet al. IDO-Orchestrated Crosstalk Between pDCs and Tregs Inhibits Autoimmunity. J Autoimmun (2016) 75:39–49. doi: 10.1016/j.jaut.2016.07.004

  • CrossRef
  • Google Scholar

• 80

  CurtiAPandolfiSValzasinaBAluigiMIsidoriAFerriEet al. Modulation of Tryptophan Catabolism by Human Leukemic Cells Results in the Conversion of CD25- Into CD25+ T Regulatory Cells. Blood (2007) 109:2871–7. doi: 10.1182/blood-2006-07-036863

  • CrossRef
  • Google Scholar

• 81

  FallarinoFGrohmannUHwangKWOrabonaCVaccaCBianchiRet al. Modulation of Tryptophan Catabolism by Regulatory T Cells. Nat Immunol (2003) 4:1206–12. doi: 10.1038/ni1003

  • CrossRef
  • Google Scholar

• 82

  JollerNLozanoEBurkettPRPatelBXiaoSZhuCet al. Treg Cells Expressing the Coinhibitory Molecule TIGIT Selectively Inhibit Proinflammatory Th1 and Th17 Cell Responses. Immunity (2014) 40:569–81. doi: 10.1016/j.immuni.2014.02.012

  • CrossRef
  • Google Scholar

• 83

  KurtulusSSakuishiKNgiowS-FJollerNTanDJTengMWLet al. TIGIT Predominantly Regulates the Immune Response via Regulatory T Cells. J Clin Invest (2015) 125:4053–62. doi: 10.1172/JCI81187

  • CrossRef
  • Google Scholar

• 84

  GuoJZhouX. Regulatory T Cells Turn Pathogenic. Cell Mol Immunol (2015) 12:525–32. doi: 10.1038/cmi.2015.12

  • CrossRef
  • Google Scholar

• 85

  KassiotisGO’GarraA. Immunology. Immunity Benefits From a Little Suppression. Science (2008) 320:1168–9. doi: 10.1126/science.1159090

  • CrossRef
  • Google Scholar

• 86

  LundJMHsingLPhamTTRudenskyAY. Coordination of Early Protective Immunity to Viral Infection by Regulatory T Cells. Science (2008) 320:1220–4. doi: 10.1126/science.1155209

  • CrossRef
  • Google Scholar

• 87

  Moreno-FernandezMERuedaCMRusieLKChougnetCA. Regulatory T Cells Control HIV Replication in Activated T Cells Through a cAMP-Dependent Mechanism. Blood (2011) 117:5372–80. doi: 10.1182/blood-2010-12-323162

  • CrossRef
  • Google Scholar

• 88

  HaaseAT. Perils at Mucosal Front Lines for HIV and SIV and Their Hosts. Nat Rev Immunol (2005) 5:783–92. doi: 10.1038/nri1706

  • CrossRef
  • Google Scholar

• 89

  GrahamJBDa CostaALundJM. Regulatory T Cells Shape the Resident Memory T Cell Response to Virus Infection in the Tissues. J Immunol (2014) 192:683–90. doi: 10.4049/jimmunol.1202153

  • CrossRef
  • Google Scholar

• 90

  ZelinskyyGDietzeKKHüseckenYPSchimmerSNairSWernerTet al. The Regulatory T-Cell Response During Acute Retroviral Infection Is Locally Defined and Controls the Magnitude and Duration of the Virus-Specific Cytotoxic T-Cell Response. Blood (2009) 114:3199–207. doi: 10.1182/blood-2009-03-208736

  • CrossRef
  • Google Scholar

• 91

  IwashiroMMesserRJPetersonKEStromnesIMSugieTHasenkrugKJ. Immunosuppression by CD4+ Regulatory T Cells Induced by Chronic Retroviral Infection. Proc Natl Acad Sci (2001) 98:9226–30. doi: 10.1073/pnas.151174198

  • CrossRef
  • Google Scholar

• 92

  HaeryfarSMMDiPaoloRJTscharkeDCBenninkJRYewdellJW. Regulatory T Cells Suppress CD8+ T Cell Responses Induced by Direct Priming and Cross-Priming and Moderate Immunodominance Disparities. J Immunol (2005) 174:3344–51. doi: 10.4049/jimmunol.174.6.3344

  • CrossRef
  • Google Scholar

• 93

  AandahlEMMichaëlssonJMorettoWJHechtFMNixonDF. Human CD4+ CD25+ Regulatory T Cells Control T-Cell Responses to Human Immunodeficiency Virus and Cytomegalovirus Antigens. J Virol (2004) 78:2454–9. doi: 10.1128/jvi.78.5.2454-2459.2004

  • CrossRef
  • Google Scholar

• 94

  HuntPWLandayALSinclairEMartinsonJAHatanoHEmuBet al. A Low T Regulatory Cell Response May Contribute to Both Viral Control and Generalized Immune Activation in HIV Controllers. PloS One (2011) 6:e15924. doi: 10.1371/journal.pone.0015924

  • CrossRef
  • Google Scholar

• 95

  HasenkrugKJChougnetCADittmerU. Regulatory T Cells in Retroviral Infections. PloS Pathog (2018) 14:e1006776. doi: 10.1371/journal.ppat.1006776

  • CrossRef
  • Google Scholar

• 96

  EggenaMPBarugahareBJonesNOkelloMMutalyaSKityoCet al. Depletion of Regulatory T Cells in HIV Infection Is Associated With Immune Activation. J Immunol (2005) 174:4407–14. doi: 10.4049/jimmunol.174.7.4407

  • CrossRef
  • Google Scholar

• 97

  Oswald-RichterKGrillSMLeelawongMUnutmazD. HIV Infection of Primary Human T Cells Is Determined by Tunable Thresholds of T Cell Activation. Eur J Immunol (2004) 34:1705–14. doi: 10.1002/eji.200424892

  • CrossRef
  • Google Scholar

• 98

  ChaseAJYangH-CZhangHBlanksonJNSilicianoRF. Preservation of FoxP3+ Regulatory T Cells in the Peripheral Blood of Human Immunodeficiency Virus Type 1-Infected Elite Suppressors Correlates With Low CD4+ T-Cell Activation. J Virol (2008) 82:8307–15. doi: 10.1128/JVI.00520-08

  • CrossRef
  • Google Scholar

• 99

  AnderssonJBoassoANilssonJZhangRShireNJLindbackSet al. The Prevalence of Regulatory T Cells in Lymphoid Tissue Is Correlated With Viral Load in HIV-Infected Patients. J Immunol (2005) 174:3143–7. doi: 10.4049/jimmunol.174.6.3143

  • CrossRef
  • Google Scholar

• 100

  KinterALHennesseyMBellAKernSLinYDaucherMet al. CD25(+)CD4(+) Regulatory T Cells From the Peripheral Blood of Asymptomatic HIV-Infected Individuals Regulate CD4(+) and CD8(+) HIV-Specific T Cell Immune Responses In Vitro and Are Associated With Favorable Clinical Markers of Disease Status. J Exp Med (2004) 200:331–43. doi: 10.1084/jem.20032069

  • CrossRef
  • Google Scholar

• 101

  WeissLDonkova-PetriniVCaccavelliLBalboMCarbonneilCLevyY. Human Immunodeficiency Virus–Driven Expansion of CD4+CD25+ Regulatory T Cells, Which Suppress HIV-Specific CD4 T-Cell Responses in HIV-Infected Patients. Blood (2004) 104:3249–56. doi: 10.1182/blood-2004-01-0365

  • CrossRef
  • Google Scholar

• 102

  AnderssonJBoassoANilssonJZhangRShireNJLindbackSet al. Cutting Edge: The Prevalence of Regulatory T Cells in Lymphoid Tissue Is Correlated With Viral Load in HIV-Infected Patients. J Immunol (2005) 174:3143–7. doi: 10.4049/jimmunol.174.6.3143

  • CrossRef
  • Google Scholar

• 103

  Oswald-RichterKGrillSMShariatNLeelawongMSundrudMSHaasDWet al. HIV Infection of Naturally Occurring and Genetically Reprogrammed Human Regulatory T-Cells. PloS Biol (2004) 2:e198. doi: 10.1371/journal.pbio.0020198

  • CrossRef
  • Google Scholar

• 104

  BolacchiFSinistroACiapriniCDeminFCapozziMCarducciFCet al. Increased Hepatitis C Virus (HCV)-Specific CD4+CD25+ Regulatory T Lymphocytes and Reduced HCV-Specific CD4+ T Cell Response in HCV-Infected Patients With Normal Versus Abnormal Alanine Aminotransferase Levels. Clin Exp Immunol (2006) 144:188–96. doi: 10.1111/j.1365-2249.2006.03048.x

  • CrossRef
  • Google Scholar

• 105

  SugimotoKIkedaFStadanlickJNunesFAAlterHJChangK-M. Suppression of HCV-Specific T Cells Without Differential Hierarchy Demonstrated Ex Vivo in Persistent HCV Infection. Hepatology (2003) 38:1437–48. doi: 10.1016/j.hep.2003.09.026

  • CrossRef
  • Google Scholar

• 106

  BoettlerTSpangenbergHCNeumann-HaefelinCPantherEUrbaniSFerrariCet al. T Cells With a CD4+CD25+ Regulatory Phenotype Suppress In Vitro Proliferation of Virus-Specific CD8+ T Cells During Chronic Hepatitis C Virus Infection. J Virol (2005) 79:7860–7. doi: 10.1128/JVI.79.12.7860-7867.2005

  • CrossRef
  • Google Scholar

• 107

  LiSJonesKLWoollardDJDromeyJPaukovicsGPlebanskiMet al. Defining Target Antigens for CD25+ FOXP3 + IFN-Gamma- Regulatory T Cells in Chronic Hepatitis C Virus Infection. Immunol Cell Biol (2007) 85:197–204. doi: 10.1038/sj.icb.7100020

  • CrossRef
  • Google Scholar

• 108

  BoyerOSaadounDAbriolJDodilleMPietteJ-CCacoubPet al. CD4+CD25+ Regulatory T-Cell Deficiency in Patients With Hepatitis C-Mixed Cryoglobulinemia Vasculitis. Blood (2004) 103:3428–30. doi: 10.1182/blood-2003-07-2598

  • CrossRef
  • Google Scholar

• 109

  CabreraRTuZXuYFirpiRJRosenHRLiuCet al. An Immunomodulatory Role for CD4(+)CD25(+) Regulatory T Lymphocytes in Hepatitis C Virus Infection. Hepatology (2004) 40:1062–71. doi: 10.1002/hep.20454

  • CrossRef
  • Google Scholar

• 110

  BelkaidYRouseBT. Natural Regulatory T Cells in Infectious Disease. Nat Immunol (2005) 6:353–60. doi: 10.1038/ni1181

  • CrossRef
  • Google Scholar

• 111

  MaloyKJSalaunLCahillRDouganGSaundersNJPowrieF. CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-Dependent Mechanisms. J Exp Med (2003) 197:111–9. doi: 10.1084/jem.20021345

  • CrossRef
  • Google Scholar

• 112

  KullbergMCJankovicDGorelickPLCasparPLetterioJJCheeverAWet al. Bacteria-Triggered CD4+ T Regulatory Cells Suppress Helicobacter Hepaticus–Induced Colitis. J Exp Med (2002) 196:505–15. doi: 10.1084/jem.20020556

  • CrossRef
  • Google Scholar

• 113

  KaparakisMLaurieKLWijburgOPedersenJPearseMvan DrielIRet al. CD4+ CD25+ Regulatory T Cells Modulate the T-Cell and Antibody Responses in Helicobacter-Infected BALB/c Mice. Infect Immun (2006) 74:3519–29. doi: 10.1128/IAI.01314-05

  • CrossRef
  • Google Scholar

• 114

  RaghavanSSuri-PayerEHolmgrenJ. Antigen-Specific In Vitro Suppression of Murine Helicobacter Pylori-Reactive Immunopathological T Cells by CD4+CD25+ Regulatory T Cells. Scand J Immunol (2004) 60:82–8. doi: 10.1111/j.0300-9475.2004.01447.x

  • CrossRef
  • Google Scholar

• 115

  LundgrenASuri-PayerEEnarssonKSvennerholmA-MLundinBS. Helicobacter Pylori- Specific CD4 ⁺ CD25 ^High Regulatory T Cells Suppress Memory T-Cell Responses to H . Pylori in Infected Individuals. Infect Immun (2003) 71:1755–62. doi: 10.1128/IAI.71.4.1755-1762.2003

  • CrossRef
  • Google Scholar

• 116

  KursarMBonhagenKFensterleJKöhlerAHurwitzRKamradtTet al. Regulatory CD4+CD25+ T Cells Restrict Memory CD8+ T Cell Responses. J Exp Med (2002) 196:1585–92. doi: 10.1084/jem.20011347

  • CrossRef
  • Google Scholar

• 117

  McKinleyLLogarAJMcAllisterFZhengMSteeleCKollsJK. Regulatory T Cells Dampen Pulmonary Inflammation and Lung Injury in an Animal Model of Pneumocystis Pneumonia. J Immunol (2006) 177:6215–26. doi: 10.4049/jimmunol.177.9.6215

  • CrossRef
  • Google Scholar

• 118

  HoriSCarvalhoTLDemengeotJ. CD25+CD4+ Regulatory T Cells Suppress CD4+ T Cell-Mediated Pulmonary Hyperinflammation Driven by Pneumocystis Carinii in Immunodeficient Mice. Eur J Immunol (2002) 32:1282–91. doi: 10.1002/1521-4141(200205)32:5<1282::AID-IMMU1282>3.0.CO;2-

  • CrossRef
  • Google Scholar

• 119

  TenorioEPOlguínJEFernándezJVieyraPSaavedraR. Reduction of Foxp 3 + Cells by Depletion With the PC61 mAb Induces Mortality in Resistant BALB/c Mice Infected With Toxoplasma Gondii. J Biomed Biotechnol (2010) 2010:1–9. doi: 10.1155/2010/786078

  • CrossRef
  • Google Scholar

• 120

  JohannsTMErteltJMRoweJHWaySS. Regulatory T Cell Suppressive Potency Dictates the Balance Between Bacterial Proliferation and Clearance During Persistent Salmonella Infection. PloS Pathog (2010) 6:e1001043. doi: 10.1371/journal.ppat.1001043

  • CrossRef
  • Google Scholar

• 121

  MonackDM. Helicobacter and Salmonella Persistent Infection Strategies. Cold Spring Harb Perspect Med (2013) 3:a010348. doi: 10.1101/cshperspect.a010348

  • CrossRef
  • Google Scholar

• 122

  NeillDRCowardWRGritzfeldJFRichardsLGarcia-GarciaFJDotorJet al. Density and Duration of Pneumococcal Carriage Is Maintained by Transforming Growth Factor β1 and T Regulatory Cells. Am J Respir Crit Care Med (2014) 189:1250–9. doi: 10.1164/rccm.201401-0128OC

  • CrossRef
  • Google Scholar

• 123

  BoerMCJoostenSAOttenhoffTHM. Regulatory T-Cells at the Interface Between Human Host and Pathogens in Infectious Diseases and Vaccination. Front Immunol (2015) 6:217. doi: 10.3389/fimmu.2015.00217

  • CrossRef
  • Google Scholar

• 124

  TrinschekBLüssiFHaasJWildemannBZippFWiendlHet al. Kinetics of IL-6 Production Defines T Effector Cell Responsiveness to Regulatory T Cells in Multiple Sclerosis. PloS One (2013) 8:e77634. doi: 10.1371/journal.pone.0077634

  • CrossRef
  • Google Scholar

• 125

  SchneiderALongSACerosalettiKNiCTSamuelsPKitaMet al. In Active Relapsing-Remitting Multiple Sclerosis, Effector T Cell Resistance to Adaptive Tregs Involves IL-6-Mediated Signaling. Sci Trans Med (2013) 5:170ra15–170ra15. doi: 10.1126/scitranslmed.3004970

  • CrossRef
  • Google Scholar

• 126

  GrossCCMeyerCBhatiaUYshiiLKleffnerIBauerJet al. CD8+ T Cell-Mediated Endotheliopathy Is a Targetable Mechanism of Neuro-Inflammation in Susac Syndrome. Nat Commun (2019) 10:5779. doi: 10.1038/s41467-019-13593-5

  • CrossRef
  • Google Scholar

• 127

  RobertsonSJMesserRJCarmodyABHasenkrugKJ. In Vitro Suppression of CD8+ T Cell Function by Friend Virus-Induced Regulatory T Cells. J Immunol (2006) 176:3342–9. doi: 10.4049/jimmunol.176.6.3342

  • CrossRef
  • Google Scholar

• 128

  ZelinskyyGKraftARMSchimmerSArndtTDittmerU. Kinetics of CD8+ Effector T Cell Responses and Induced CD4+ Regulatory T Cell Responses During Friend Retrovirus Infection. Eur J Immunol (2006) 36:2658–70. doi: 10.1002/eji.200636059

  • CrossRef
  • Google Scholar

• 129

  HeHMesserRJSakaguchiSYangGRobertsonSJHasenkrugKJ. Reduction of Retrovirus-Induced Immunosuppression by In Vivo Modulation of T Cells During Acute Infection. J Virol (2004) 78:11641–7. doi: 10.1128/JVI.78.21.11641-11647.2004

  • CrossRef
  • Google Scholar

• 130

  DittmerUHeHMesserRJSchimmerSOlbrichARMOhlenCet al. Functional Impairment of CD8+ T Cells by Regulatory T Cells During Persistent Retroviral Infection. Immunity (2004) 20:293–303. doi: 10.1016/S1074-7613(04)00054-8

  • CrossRef
  • Google Scholar

• 131

  SuvasSAzkurAKKimBSKumaraguruURouseBT. CD4 ⁺ CD25 ⁺ Regulatory T Cells Control the Severity of Viral Immunoinflammatory Lesions. J Immunol (2004) 172:4123–32. doi: 10.4049/jimmunol.172.7.4123

  • CrossRef
  • Google Scholar

• 132

  SuvasSKumaraguruUPackCDLeeSRouseBT. CD4+CD25+ T Cells Regulate Virus-Specific Primary and Memory CD8+ T Cell Responses. J Exp Med (2003) 198:889–901. doi: 10.1084/jem.20030171

  • CrossRef
  • Google Scholar

• 133

  MyersLMesserRJCarmodyABHasenkrugKJ. Tissue-Specific Abundance of Regulatory T Cells Correlates With CD8+ T Cell Dysfunction and Chronic Retrovirus Loads. J Immunol (2009) 183:1636–43. doi: 10.4049/jimmunol.0900350

  • CrossRef
  • Google Scholar

• 134

  MyersLHasenkrugKJ. Retroviral Immunology: Lessons From a Mouse Model. Immunol Res (2009) 43:160–6. doi: 10.1007/s12026-008-8061-x

  • CrossRef
  • Google Scholar

• 135

  KinterAMcNallyJRigginLJacksonRRobyGFauciAS. Suppression of HIV-Specific T Cell Activity by Lymph Node CD25+ Regulatory T Cells From HIV-Infected Individuals. Proc Natl Acad Sci USA (2007) 104:3390–5. doi: 10.1073/pnas.0611423104

  • CrossRef
  • Google Scholar

• 136

  WanZZhouZLiuYLaiYLuoYPengXet al. Regulatory T Cells and T Helper 17 Cells in Viral Infection. Scand J Immunol (2020) 91:e12873. doi: 10.1111/sji.12873

  • CrossRef
  • Google Scholar

• 137

  ShafianiSTucker-HeardGKariyoneATakatsuKUrdahlKB. Pathogen-Specific Regulatory T Cells Delay the Arrival of Effector T Cells in the Lung During Early Tuberculosis. J Exp Med (2010) 207:1409–20. doi: 10.1084/jem.20091885

  • CrossRef
  • Google Scholar

• 138

  ShafianiSDinhCErteltJMMogucheAOSiddiquiISmigielKSet al. Pathogen-Specific Treg Cells Expand Early During Mycobacterium Tuberculosis Infection But Are Later Eliminated in Response to Interleukin-12. Immunity (2013) 38:1261–70. doi: 10.1016/j.immuni.2013.06.003

  • CrossRef
  • Google Scholar

• 139

  Scott-BrowneJPShafianiSTucker-HeardGIshida-TsubotaKFontenotJDRudenskyAYet al. Expansion and Function of Foxp3-Expressing T Regulatory Cells During Tuberculosis. J Exp Med (2007) 204:2159–69. doi: 10.1084/jem.20062105

  • CrossRef
  • Google Scholar

• 140

  ChenXZhouBLiMDengQWuXLeXet al. CD4(+)CD25(+)FoxP3(+) Regulatory T Cells Suppress Mycobacterium Tuberculosis Immunity in Patients With Active Disease. Clin Immunol (2007) 123:50–9. doi: 10.1016/j.clim.2006.11.009

  • CrossRef
  • Google Scholar

• 141

  Ribeiro-RodriguesRResende CoTRojasRToossiZDietzeRBoomWHet al. A Role for CD4+CD25+ T Cells in Regulation of the Immune Response During Human Tuberculosis. Clin Exp Immunol (2006) 144:25–34. doi: 10.1111/j.1365-2249.2006.03027.x

  • CrossRef
  • Google Scholar

• 142

  Guyot-RevolVInnesJAHackforthSHinksTLalvaniA. Regulatory T Cells Are Expanded in Blood and Disease Sites in Patients With Tuberculosis. Am J Respir Crit Care Med (2006) 173:803–10. doi: 10.1164/rccm.200508-1294OC

  • CrossRef
  • Google Scholar

• 143

  XuDFuJJinLZhangHZhouCZouZet al. Circulating and Liver Resident CD4+CD25+ Regulatory T Cells Actively Influence the Antiviral Immune Response and Disease Progression in Patients With Hepatitis B. J Immunol (2006) 177:739–47. doi: 10.4049/jimmunol.177.1.739

  • CrossRef
  • Google Scholar

• 144

  YangGLiuAXieQGuoTBWanBZhouBet al. Association of CD4+CD25+Foxp3+ Regulatory T Cells With Chronic Activity and Viral Clearance in Patients With Hepatitis B. Int Immunol (2007) 19:133–40. doi: 10.1093/intimm/dxl130

  • CrossRef
  • Google Scholar

• 145

  StoopJNvan der MolenRGKuipersEJKustersJGJanssenHLA. Inhibition of Viral Replication Reduces Regulatory T Cells and Enhances the Antiviral Immune Response in Chronic Hepatitis B. Virology (2007) 361:141–8. doi: 10.1016/j.virol.2006.11.018

  • CrossRef
  • Google Scholar

• 146

  MontagnoliCBacciABozzaSGazianoRMosciPSharpeAHet al. B7/CD28-Dependent CD4 ⁺ CD25 ⁺ Regulatory T Cells Are Essential Components of the Memory-Protective Immunity to Candida albicans. J Immunol (2002) 169:6298–308. doi: 10.4049/jimmunol.169.11.6298

  • CrossRef
  • Google Scholar

• 147

  NeteaMGJoostenLABLatzEMillsKHGNatoliGStunnenbergHGet al. Trained Immunity: A Program of Innate Immune Memory in Health and Disease. Science (2016) 352:aaf1098. doi: 10.1126/science.aaf1098

  • CrossRef
  • Google Scholar

• 148

  CaiX-PZhangHZhangY-CWangYSuCJiM-Jet al. Dynamics of CD4+CD25+ T Cells in Spleens and Mesenteric Lymph Nodes of Mice Infected With Schistosoma Japonicum. Acta Biochim Biophys Sin (Shanghai) (2006) 38:299–304. doi: 10.1111/j.1745-7270.2006.00168.x

  • CrossRef
  • Google Scholar

• 149

  HesseMPiccirilloCABelkaidYPruferJMentink-KaneMLeusinkMet al. The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells. J Immunol (2004) 172:3157–66. doi: 10.4049/jimmunol.172.5.3157

  • CrossRef
  • Google Scholar

• 150

  CampanelliAPRoselinoAMCavassaniKAPereiraMSFMortaraRABrodskynCIet al. CD4+CD25+ T Cells in Skin Lesions of Patients With Cutaneous Leishmaniasis Exhibit Phenotypic and Functional Characteristics of Natural Regulatory T Cells. J Infect Dis (2006) 193:1313–22. doi: 10.1086/502980

  • CrossRef
  • Google Scholar

• 151

  AseffaAGumyALaunoisPMacDonaldHRLouisJATacchini-CottierF. The Early IL-4 Response to Leishmania Major and the Resulting Th2 Cell Maturation Steering Progressive Disease in BALB/c Mice Are Subject to the Control of Regulatory CD4 ⁺ CD25 ⁺ T Cells. J Immunol (2002) 169:3232–41. doi: 10.4049/jimmunol.169.6.3232

  • CrossRef
  • Google Scholar

• 152

  XuDLiuHKomai-KomaMCampbellCMcSharryCAlexanderJet al. CD4 ⁺ CD25 ⁺ Regulatory T Cells Suppress Differentiation and Functions of Th1 and Th2 Cells, Leishmania Major Infection, and Colitis in Mice. J Immunol (2003) 170:394–9. doi: 10.4049/jimmunol.170.1.394

  • CrossRef
  • Google Scholar

• 153

  MendezSRecklingSKPiccirilloCASacksDBelkaidY. Role for CD4+ CD25+ Regulatory T Cells in Reactivation of Persistent Leishmaniasis and Control of Concomitant Immunity. J Exp Med (2004) 200:201–10. doi: 10.1084/jem.20040298

  • CrossRef
  • Google Scholar

• 154

  BelkaidYPiccirilloCAMendezSShevachEMSacksDL. CD4+CD25+ Regulatory T Cells Control Leishmania Major Persistence and Immunity. Nature (2002) 420:502–7. doi: 10.1038/nature01152

  • CrossRef
  • Google Scholar

• 155

  LiuHHuBXuDLiewFY. CD4 ⁺ CD25 ⁺ Regulatory T Cells Cure Murine Colitis: The Role of IL-10, TGF-β, and CTLA4. J Immunol (2003) 171:5012–7. doi: 10.4049/jimmunol.171.10.5012

  • CrossRef
  • Google Scholar

• 156

  KitagakiKBusingaTRRacilaDElliottDEWeinstockJVKlineJN. Intestinal Helminths Protect in a Murine Model of Asthma. J Immunol (2006) 177:1628–35. doi: 10.4049/jimmunol.177.3.1628

  • CrossRef
  • Google Scholar

• 157

  McKeeASPearceEJ. CD25 ⁺ CD4 ⁺ Cells Contribute to Th2 Polarization During Helminth Infection by Suppressing Th1 Response Development. J Immunol (2004) 173:1224–31. doi: 10.4049/jimmunol.173.2.1224

  • CrossRef
  • Google Scholar

• 158

  TaylorJJMohrsMPearceEJ. Regulatory T Cell Responses Develop in Parallel to Th Responses and Control the Magnitude and Phenotype of the Th Effector Population. J Immunol (2006) 176:5839–47. doi: 10.4049/jimmunol.176.10.5839

  • CrossRef
  • Google Scholar

• 159

  JinRMBlairSJWarunekJHeffnerRRBladerIJWohlfertEA. Regulatory T Cells Promote Myositis and Muscle Damage in Toxoplasma Gondii Infection. J Immunol (2017) 198:352–62. doi: 10.4049/jimmunol.1600914

  • CrossRef
  • Google Scholar

• 160

  SehrawatSRouseBT. Interplay of Regulatory T Cell and Th17 Cells During Infectious Diseases in Humans and Animals. Front Immunol (2017) 8:341. doi: 10.3389/fimmu.2017.00341

  • CrossRef
  • Google Scholar

• 161

  TesmerLALundySKSarkarSFoxDA. Th17 Cells in Human Disease. Immunol Rev (2008) 223:87–113. doi: 10.1111/j.1600-065X.2008.00628.x

  • CrossRef
  • Google Scholar

• 162

  WeaverCTHarringtonLEManganPRGavrieliMMurphyKM. Th17: An Effector CD4 T Cell Lineage With Regulatory T Cell Ties. Immunity (2006) 24:677–88. doi: 10.1016/j.immuni.2006.06.002

  • CrossRef
  • Google Scholar

• 163

  DenningTLWangYPatelSRWilliamsIRPulendranB. Lamina Propria Macrophages and Dendritic Cells Differentially Induce Regulatory and Interleukin 17-Producing T Cell Responses. Nat Immunol (2007) 8:1086–94. doi: 10.1038/ni1511

  • CrossRef
  • Google Scholar

• 164

  AwasthiAKuchrooVK. Th17 Cells: From Precursors to Players in Inflammation and Infection. Int Immunol (2009) 21:489–98. doi: 10.1093/intimm/dxp021

  • CrossRef
  • Google Scholar

• 165

  KimuraAKishimotoT. IL-6: Regulator of Treg/Th17 Balance. Eur J Immunol (2010) 40:1830–5. doi: 10.1002/eji.201040391

  • CrossRef
  • Google Scholar

• 166

  WuBWanY. Molecular Control of Pathogenic Th17 Cells in Autoimmune Diseases. Int Immunopharmacol (2020) 80:106187. doi: 10.1016/j.intimp.2020.106187

  • CrossRef
  • Google Scholar

• 167

  RevuSWuJHenkelMRittenhouseNMenkADelgoffeGMet al. IL-23 and IL-1β Drive Human Th17 Cell Differentiation and Metabolic Reprogramming in Absence of CD28 Costimulation. Cell Rep (2018) 22:2642–53. doi: 10.1016/j.celrep.2018.02.044

  • CrossRef
  • Google Scholar

• 168

  ToussirotE. The IL23/Th17 Pathway as a Therapeutic Target in Chronic Inflammatory Diseases. Inflamm Allergy Drug Targets (2012) 11:159–68. doi: 10.2174/187152812800392805

  • CrossRef
  • Google Scholar

• 169

  BiYYangR. Direct and Indirect Regulatory Mechanisms in TH17 Cell Differentiation and Functions: Direct and Indirect Regulatory Mechanisms in TH17 Cell. Scand J Immunol (2012) 75:543–52. doi: 10.1111/j.1365-3083.2012.02686.x

  • CrossRef
  • Google Scholar

• 170

  TranDQ. TGF-β: The Sword, the Wand, and the Shield of FOXP3(+) Regulatory T Cells. J Mol Cell Biol (2012) 4:29–37. doi: 10.1093/jmcb/mjr033

  • CrossRef
  • Google Scholar

• 171

  LiMOFlavellRA. TGF-β: A Master of All T Cell Trades. Cell (2008) 134:392–404. doi: 10.1016/j.cell.2008.07.025

  • CrossRef
  • Google Scholar

• 172

  ZhouLChongMMWLittmanDR. Plasticity of CD4+ T Cell Lineage Differentiation. Immunity (2009) 30:646–55. doi: 10.1016/j.immuni.2009.05.001

  • CrossRef
  • Google Scholar

• 173

  Di CesareADi MeglioPNestleFO. The IL-23/Th17 Axis in the Immunopathogenesis of Psoriasis. J Invest Dermatol (2009) 129:1339–50. doi: 10.1038/jid.2009.59

  • CrossRef
  • Google Scholar

• 174

  Suri-PayerEAmarAZThorntonAMShevachEM. CD4+CD25+ T Cells Inhibit Both the Induction and Effector Function of Autoreactive T Cells and Represent a Unique Lineage of Immunoregulatory Cells. J Immunol (1998) 160:1212–8.

  • Google Scholar

• 175

  SadeghiATahmasebiSMahmoodAKuznetsovaMValizadehHTaghizadiehAet al. Th17 and Treg Cells Function in SARS-CoV2 Patients Compared With Healthy Controls. J Cell Physiol (2021) 236:2829–39. doi: 10.1002/jcp.30047

  • CrossRef
  • Google Scholar

• 176

  AnnunziatoFCosmiLSantarlasciVMaggiLLiottaFMazzinghiBet al. Phenotypic and Functional Features of Human Th17 Cells. J Exp Med (2007) 204:1849–61. doi: 10.1084/jem.20070663

  • CrossRef
  • Google Scholar

• 177

  QinLHuCFengJXiaQ. Activation of Lymphocytes Induced by Bronchial Epithelial Cells With Prolonged RSV Infection. PloS One (2011) 6:e27113. doi: 10.1371/journal.pone.0027113

  • CrossRef
  • Google Scholar

• 178

  HoeEAndersonJNathanielszJTohZQMarimlaRBallochAet al. The Contrasting Roles of Th17 Immunity in Human Health and Disease. Microbiol Immunol (2017) 61:49–56. doi: 10.1111/1348-0421.12471

  • CrossRef
  • Google Scholar

• 179

  WuY-CChenC-SChanY-J. The Outbreak of COVID-19: An Overview. J Chin Med Assoc (2020) 83:217–20. doi: 10.1097/JCMA.0000000000000270

  • CrossRef
  • Google Scholar

• 180

  MangodtTCVan HerckMANullensSRametJDe DooyJJJorensPGet al. The Role of Th17 and Treg Responses in the Pathogenesis of RSV Infection. Pediatr Res (2015) 78:483–91. doi: 10.1038/pr.2015.143

  • CrossRef
  • Google Scholar

• 181

  LuXMcCoyKSXuJHuWChenHJiangKet al. Galectin-9 Ameliorates Respiratory Syncytial Virus-Induced Pulmonary Immunopathology Through Regulating the Balance Between Th17 and Regulatory T Cells. Virus Res (2015) 195:162–71. doi: 10.1016/j.virusres.2014.10.011

  • CrossRef
  • Google Scholar

• 182

  FultonRBMeyerholzDKVargaSM. Foxp3 ⁺ CD4 Regulatory T Cells Limit Pulmonary Immunopathology by Modulating the CD8 T Cell Response During Respiratory Syncytial Virus Infection. J Immunol (2010) 185:2382–92. doi: 10.4049/jimmunol.1000423

  • CrossRef
  • Google Scholar

• 183

  LeeDCPHarkerJAETregoningJSAtabaniSFJohanssonCSchwarzeJet al. CD25 ⁺ Natural Regulatory T Cells Are Critical in Limiting Innate and Adaptive Immunity and Resolving Disease Following Respiratory Syncytial Virus Infection. J Virol (2010) 84:8790–8. doi: 10.1128/JVI.00796-10

  • CrossRef
  • Google Scholar

• 184

  RuckwardtTJBonaparteKLNasonMCGrahamBS. Regulatory T Cells Promote Early Influx of CD8 ⁺ T Cells in the Lungs of Respiratory Syncytial Virus-Infected Mice and Diminish Immunodominance Disparities. J Virol (2009) 83:3019–28. doi: 10.1128/JVI.00036-09

  • CrossRef
  • Google Scholar

• 185

  LoebbermannJThorntonHDurantLSparwasserTWebsterKESprentJet al. Regulatory T Cells Expressing Granzyme B Play a Critical Role in Controlling Lung Inflammation During Acute Viral Infection. Mucosal Immunol (2012) 5:161–72. doi: 10.1038/mi.2011.62

  • CrossRef
  • Google Scholar

• 186

  DurantLRMakrisSVoorburgCMLoebbermannJJohanssonCOpenshawPJM. Regulatory T Cells Prevent Th2 Immune Responses and Pulmonary Eosinophilia During Respiratory Syncytial Virus Infection in Mice. J Virol (2013) 87:10946–54. doi: 10.1128/JVI.01295-13

  • CrossRef
  • Google Scholar

• 187

  MukherjeeSLindellDMBerlinAAMorrisSBShanleyTPHershensonMBet al. IL-17–Induced Pulmonary Pathogenesis During Respiratory Viral Infection and Exacerbation of Allergic Disease. Am J Pathol (2011) 179:248–58. doi: 10.1016/j.ajpath.2011.03.003

  • CrossRef
  • Google Scholar

• 188

  BystromJAl-AdhoubiNAl-BogamiMJawadAMageedR. Th17 Lymphocytes in Respiratory Syncytial Virus Infection. Viruses (2013) 5:777–91. doi: 10.3390/v5030777

  • CrossRef
  • Google Scholar

• 189

  ChenYFangJChenXPanCLiuXLiuJ. Effects of the Treg/Th17 Cell Balance and Their Associated Cytokines in Patients With Hepatitis B Infection. Exp Ther Med (2015) 9:573–8. doi: 10.3892/etm.2014.2104

  • CrossRef
  • Google Scholar

• 190

  LanY-TWangZTianPGongX-NFanY-CWangK. Treg/Th17 Imbalance and Its Clinical Significance in Patients With Hepatitis B-Associated Liver Cirrhosis. Diagn Pathol (2019) 14:114. doi: 10.1186/s13000-019-0891-4

  • CrossRef
  • Google Scholar

• 191

  RowanAGFletcherJMRyanEJMoranBHegartyJEO’FarrellyCet al. Hepatitis C Virus-Specific Th17 Cells Are Suppressed by Virus-Induced TGF-Beta. J Immunol (2008) 181:4485–94. doi: 10.4049/jimmunol.181.7.4485

  • CrossRef
  • Google Scholar

• 192

  CardonaPCardonaP-J. Regulatory T Cells in Mycobacterium Tuberculosis Infection. Front Immunol (2019) 10:2139. doi: 10.3389/fimmu.2019.02139

  • CrossRef
  • Google Scholar

• 193

  Adibzadeh SereshgiMMAbdollahpour-AlitappehMMahdaviMRanjbarRAhmadiKTaheriRAet al. Immunologic Balance of Regulatory T Cell/T Helper 17 Responses in Gastrointestinal Infectious Diseases: Role of miRNAs. Microb Pathog (2019) 131:135–43. doi: 10.1016/j.micpath.2019.03.029

  • CrossRef
  • Google Scholar

• 194

  Silva-CampaEFlores-MendozaLReséndizMPinelli-SaavedraAMata-HaroVMwangiWet al. Induction of T Helper 3 Regulatory Cells by Dendritic Cells Infected With Porcine Reproductive and Respiratory Syndrome Virus. Virology (2009) 387:373–9. doi: 10.1016/j.virol.2009.02.033

  • CrossRef
  • Google Scholar

• 195

  CecereTEToddSMLeroithT. Regulatory T Cells in Arterivirus and Coronavirus Infections: Do They Protect Against Disease or Enhance It? Viruses (2012) 4:833–46. doi: 10.3390/v4050833

  • CrossRef
  • Google Scholar

• 196

  LiSGowansEJChougnetCPlebanskiMDittmerU. Natural Regulatory T Cells and Persistent Viral Infection. J Virol (2008) 82:21–30. doi: 10.1128/JVI.01768-07

  • CrossRef
  • Google Scholar

• 197

  BelkaidY. Regulatory T Cells and Infection: A Dangerous Necessity. Nat Rev Immunol (2007) 7:875–88. doi: 10.1038/nri2189

  • CrossRef
  • Google Scholar

• 198

  KalfaogluBAlmeida-SantosJTyeCASatouYOnoM. T-Cell Hyperactivation and Paralysis in Severe COVID-19 Infection Revealed by Single-Cell Analysis. Front Immunol (2020) 11:589380. doi: 10.3389/fimmu.2020.589380

  • CrossRef
  • Google Scholar

• 199

  ZikloNHustonWMTaingKTimmsP. High Expression of IDO1 and TGF-β1 During Recurrence and Post Infection Clearance With Chlamydia Trachomatis, Are Independent of Host IFN-γ Response. BMC Infect Dis (2019) 19:218. doi: 10.1186/s12879-019-3843-4

  • CrossRef
  • Google Scholar

• 200

  DíazYRRojasRValderramaLSaraviaNG. T-Bet, GATA-3, and Foxp3 Expression and Th1/Th2 Cytokine Production in the Clinical Outcome of Human Infection With Leishmania (Viannia) Species. J Infect Dis (2010) 202:406–15. doi: 10.1086/653829

  • CrossRef
  • Google Scholar

• 201

  GraingerJRSmithKAHewitsonJPMcSorleyHJHarcusYFilbeyKJet al. Helminth Secretions Induce De Novo T Cell Foxp3 Expression and Regulatory Function Through the TGF-β Pathway. J Exp Med (2010) 207:2331–41. doi: 10.1084/jem.20101074

  • CrossRef
  • Google Scholar

• 202

  KleinewietfeldMHaflerDA. Regulatory T Cells in Autoimmune Neuroinflammation. Immunol Rev (2014) 259:231–44. doi: 10.1111/imr.12169

  • CrossRef
  • Google Scholar

• 203

  PetteMFujitaKKitzeBWhitakerJNAlbertEKapposLet al. Myelin Basic Protein-Specific T Lymphocyte Lines From MS Patients and Healthy Individuals. Neurology (1990) 40:1770–6. doi: 10.1212/wnl.40.11.1770

  • CrossRef
  • Google Scholar

• 204

  MykickiNHerrmannAMSchwabNDeenenRSparwasserTLimmerAet al. Melanocortin-1 Receptor Activation Is Neuroprotective in Mouse Models of Neuroinflammatory Disease. Sci Transl Med (2016) 8:362ra146. doi: 10.1126/scitranslmed.aaf8732

  • CrossRef
  • Google Scholar

• 205

  KoutrolosMBererKKawakamiNWekerleHKrishnamoorthyG. Treg Cells Mediate Recovery From EAE by Controlling Effector T Cell Proliferation and Motility in the CNS. Acta Neuropathol Commun (2014) 2:163. doi: 10.1186/s40478-014-0163-1

  • CrossRef
  • Google Scholar

• 206

  GöbelKBittnerSMelzerNPankratzSDreykluftASchuhmannMKet al. CD4(+) CD25(+) FoxP3(+) Regulatory T Cells Suppress Cytotoxicity of CD8(+) Effector T Cells: Implications for Their Capacity to Limit Inflammatory Central Nervous System Damage at the Parenchymal Level. J Neuroinflammation (2012) 9:41. doi: 10.1186/1742-2094-9-41

  • CrossRef
  • Google Scholar

• 207

  FengYArveyAChinenTvan der VeekenJGasteigerGRudenskyAY. Control of the Inheritance of Regulatory T Cell Identity by a Cis Element in the Foxp3 Locus. Cell (2014) 158:749–63. doi: 10.1016/j.cell.2014.07.031

  • CrossRef
  • Google Scholar

• 208

  KimJLahlKHoriSLoddenkemperCChaudhryAdeRoosPet al. Cutting Edge: Depletion of Foxp3+ Cells Leads to Induction of Autoimmunity by Specific Ablation of Regulatory T Cells in Genetically Targeted Mice. J Immunol (2009) 183:7631–4. doi: 10.4049/jimmunol.0804308

  • CrossRef
  • Google Scholar

• 209

  HuehnJPolanskyJKHamannA. Epigenetic Control of FOXP3 Expression: The Key to a Stable Regulatory T-Cell Lineage? Nat Rev Immunol (2009) 9:83–9. doi: 10.1038/nri2474

  • CrossRef
  • Google Scholar

• 210

  LiXLiangYLeBlancMBennerCZhengY. Function of a Foxp3 Cis-Element in Protecting Regulatory T Cell Identity. Cell (2014) 158:734–48. doi: 10.1016/j.cell.2014.07.030

  • CrossRef
  • Google Scholar

• 211

  BennettCLChristieJRamsdellFBrunkowMEFergusonPJWhitesellLet al. The Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome (IPEX) Is Caused by Mutations of FOXP3. Nat Genet (2001) 27:20–1. doi: 10.1038/83713

  • CrossRef
  • Google Scholar

• 212

  Bailey-BucktroutSLMartinez-LlordellaMZhouXAnthonyBRosenthalWLucheHet al. Self-Antigen-Driven Activation Induces Instability of Regulatory T Cells During an Inflammatory Autoimmune Response. Immunity (2013) 39:949–62. doi: 10.1016/j.immuni.2013.10.016

  • CrossRef
  • Google Scholar

• 213

  ZhouXBailey-BucktroutSLJekerLTPenarandaCMartínez-LlordellaMAshbyMet al. Instability of the Transcription Factor Foxp3 Leads to the Generation of Pathogenic Memory T Cells In Vivo. Nat Immunol (2009) 10:1000–7. doi: 10.1038/ni.1774

  • CrossRef
  • Google Scholar

• 214

  YangXONurievaRMartinezGJKangHSChungYPappuBPet al. Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs. Immunity (2008) 29:44–56. doi: 10.1016/j.immuni.2008.05.007

  • CrossRef
  • Google Scholar

• 215

  SetoguchiRHoriSTakahashiTSakaguchiS. Homeostatic Maintenance of Natural Foxp3(+) CD25(+) CD4(+) Regulatory T Cells by Interleukin (IL)-2 and Induction of Autoimmune Disease by IL-2 Neutralization. J Exp Med (2005) 201:723–35. doi: 10.1084/jem.20041982

  • CrossRef
  • Google Scholar

• 216

  PankratzSBittnerSHerrmannAMSchuhmannMKRuckTMeuthSGet al. Human CD4+ HLA-G+ Regulatory T Cells Are Potent Suppressors of Graft-Versus-Host Disease In Vivo. FASEB J (2014) 28:3435–45. doi: 10.1096/fj.14-251074

  • CrossRef
  • Google Scholar

• 217

  WaschbischASchwabNRuckTStennerM-PWiendlH. FOXP3+ T Regulatory Cells in Idiopathic Inflammatory Myopathies. J Neuroimmunol (2010) 225:137–42. doi: 10.1016/j.jneuroim.2010.03.013

  • CrossRef
  • Google Scholar

• 218

  GöbelKPankratzSAsaridouC-MHerrmannAMBittnerSMerkerMet al. Blood Coagulation Factor XII Drives Adaptive Immunity During Neuroinflammation via CD87-Mediated Modulation of Dendritic Cells. Nat Commun (2016) 7:11626. doi: 10.1038/ncomms11626

  • CrossRef
  • Google Scholar

• 219

  HeylenMRuyssersNEGielisEMVanhomwegenEPelckmansPAMoreelsTGet al. Of Worms, Mice and Man: An Overview of Experimental and Clinical Helminth-Based Therapy for Inflammatory Bowel Disease. Pharmacol Ther (2014) 143:153–67. doi: 10.1016/j.pharmthera.2014.02.011

  • CrossRef
  • Google Scholar

• 220

  BettelliEKornTOukkaMKuchrooVK. Induction and Effector Functions of TH17 Cells. Nature (2008) 453:1051–7. doi: 10.1038/nature07036

  • CrossRef
  • Google Scholar

• 221

  ChabaudMDurandJMBuchsNFossiezFPageGFrappartLet al. Human Interleukin-17: A T Cell-Derived Proinflammatory Cytokine Produced by the Rheumatoid Synovium. Arthritis Rheum (1999) 42:963–70. doi: 10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO;2-E

  • CrossRef
  • Google Scholar

• 222

  LockCHermansGPedottiRBrendolanASchadtEGarrenHet al. Gene-Microarray Analysis of Multiple Sclerosis Lesions Yields New Targets Validated in Autoimmune Encephalomyelitis. Nat Med (2002) 8:500–8. doi: 10.1038/nm0502-500

  • CrossRef
  • Google Scholar

• 223

  KleinewietfeldMHaflerDA. The Plasticity of Human Treg and Th17 Cells and Its Role in Autoimmunity. Semin Immunol (2013) 25:305–12. doi: 10.1016/j.smim.2013.10.009

  • CrossRef
  • Google Scholar

• 224

  NoackMMiossecP. Th17 and Regulatory T Cell Balance in Autoimmune and Inflammatory Diseases. Autoimmun Rev (2014) 13:668–77. doi: 10.1016/j.autrev.2013.12.004

  • CrossRef
  • Google Scholar

• 225

  KnochelmannHMDwyerCJBaileySRAmayaSMElstonDMMazza-McCrannJMet al. When Worlds Collide: Th17 and Treg Cells in Cancer and Autoimmunity. Cell Mol Immunol (2018) 15:458–69. doi: 10.1038/s41423-018-0004-4

  • CrossRef
  • Google Scholar

• 226

  RiouJAlthausCL. Pattern of Early Human-to-Human Transmission of Wuhan 2019 Novel Coronavirus (2019-nCoV), December 2019 to January 2020. Eurosurveillance (2020) 25:7–11. doi: 10.2807/1560-7917.ES.2020.25.4.2000058

  • CrossRef
  • Google Scholar

• 227

  FaschingPStradnerMGraningerWDejacoCFesslerJ. Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders. Molecules (2017) 22:134. doi: 10.3390/molecules22010134

  • CrossRef
  • Google Scholar

• 228

  SamsonMAudiaSJanikashviliNCiudadMTradMFraszczakJet al. Brief Report: Inhibition of Interleukin-6 Function Corrects Th17/Treg Cell Imbalance in Patients With Rheumatoid Arthritis. Arthritis Rheum (2012) 64:2499–503. doi: 10.1002/art.34477

  • CrossRef
  • Google Scholar

• 229

  KikuchiJHashizumeMKanekoYYoshimotoKNishinaNTakeuchiT. Peripheral Blood CD4+CD25+CD127low Regulatory T Cells Are Significantly Increased by Tocilizumab Treatment in Patients With Rheumatoid Arthritis: Increase in Regulatory T Cells Correlates With Clinical Response. Arthritis Res Ther (2015) 17:10. doi: 10.1186/s13075-015-0526-4

  • CrossRef
  • Google Scholar

• 230

  LiSWuZLiLLiuX. Interleukin-6 (IL-6) Receptor Antagonist Protects Against Rheumatoid Arthritis. Med Sci Monit (2016) 22:2113–8. doi: 10.12659/MSM.896355

  • CrossRef
  • Google Scholar

• 231

  LeeJBaekSLeeJLeeJLeeD-GParkM-Ket al. Digoxin Ameliorates Autoimmune Arthritis via Suppression of Th17 Differentiation. Int Immunopharmacol (2015) 26:103–11. doi: 10.1016/j.intimp.2015.03.017

  • CrossRef
  • Google Scholar

• 232

  WaismanAJohannL. Antigen-Presenting Cell Diversity for T Cell Reactivation in Central Nervous System Autoimmunity. J Mol Med (2018) 96:1279–92. doi: 10.1007/s00109-018-1709-7

  • CrossRef
  • Google Scholar

• 233

  PrinzMPrillerJ. The Role of Peripheral Immune Cells in the CNS in Steady State and Disease. Nat Neurosci (2017) 20:136–44. doi: 10.1038/nn.4475

  • CrossRef
  • Google Scholar

• 234

  EngelhardtBRansohoffRM. Capture, Crawl, Cross: The T Cell Code to Breach the Blood-Brain Barriers. Trends Immunol (2012) 33:579–89. doi: 10.1016/j.it.2012.07.004

  • CrossRef
  • Google Scholar

• 235

  VenkenKHellingsNBroekmansTHensenKRummensJ-LStinissenP. Natural Naive CD4+CD25+CD127low Regulatory T Cell (Treg) Development and Function Are Disturbed in Multiple Sclerosis Patients: Recovery of Memory Treg Homeostasis During Disease Progression. J Immunol (2008) 180:6411–20. doi: 10.4049/jimmunol.180.9.6411

  • CrossRef
  • Google Scholar

• 236

  Dominguez-VillarMBaecher-AllanCMHaflerDA. Identification of T Helper Type 1-Like, Foxp3+ Regulatory T Cells in Human Autoimmune Disease. Nat Med (2011) 17:673–5. doi: 10.1038/nm.2389

  • CrossRef
  • Google Scholar

• 237

  BorsellinoGKleinewietfeldMDi MitriDSternjakADiamantiniAGiomettoRet al. Expression of Ectonucleotidase CD39 by Foxp3+ Treg Cells: Hydrolysis of Extracellular ATP and Immune Suppression. Blood (2007) 110:1225–32. doi: 10.1182/blood-2006-12-064527

  • CrossRef
  • Google Scholar

• 238

  VenkenKHellingsNThewissenMSomersVHensenKRummensJ-Let al. Compromised CD4+ CD25(high) Regulatory T-Cell Function in Patients With Relapsing-Remitting Multiple Sclerosis Is Correlated With a Reduced Frequency of FOXP3-Positive Cells and Reduced FOXP3 Expression at the Single-Cell Level. Immunology (2008) 123:79–89. doi: 10.1111/j.1365-2567.2007.02690.x

  • CrossRef
  • Google Scholar

• 239

  CaoYGoodsBARaddassiKNepomGTKwokWWLoveJCet al. Functional Inflammatory Profiles Distinguish Myelin-Reactive T Cells From Patients With Multiple Sclerosis. Sci Transl Med (2015) 7:287ra74. doi: 10.1126/scitranslmed.aaa8038

  • CrossRef
  • Google Scholar

• 240

  MatuseviciusDKivisäkkPHeBKostulasNOzenciVFredriksonSet al. Interleukin-17 mRNA Expression in Blood and CSF Mononuclear Cells Is Augmented in Multiple Sclerosis. Mult Scler (1999) 5:101–4. doi: 10.1177/135245859900500206

  • CrossRef
  • Google Scholar

• 241

  VigliettaVBaecher-AllanCWeinerHLHaflerDA. Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients With Multiple Sclerosis. J Exp Med (2004) 199:971–9. doi: 10.1084/jem.20031579

  • CrossRef
  • Google Scholar

• 242

  KimuraK. Regulatory T Cells in Multiple Sclerosis. Clin Exp Neuroimmunol (2020) 11:148–55. doi: 10.1111/cen3.12591

  • CrossRef
  • Google Scholar

• 243

  FrisulloGNocitiVIorioRPatanellaAKCaggiulaMMartiAet al. Regulatory T Cells Fail to Suppress CD4T+-Bet+ T Cells in Relapsing Multiple Sclerosis Patients. Immunology (2009) 127:418–28. doi: 10.1111/j.1365-2567.2008.02963.x

  • CrossRef
  • Google Scholar

• 244

  ChenXWinkler-PickettRTCarbonettiNHOrtaldoJROppenheimJJHowardOMZ. Pertussis Toxin as an Adjuvant Suppresses the Number and Function of CD4+CD25+ T Regulatory Cells. Eur J Immunol (2006) 36:671–80. doi: 10.1002/eji.200535353

  • CrossRef
  • Google Scholar

• 245

  OthySJairamanADynesJLDongTXTuneCYerominAVet al. Regulatory T Cells Suppress Th17 Cell Ca ²⁺ Signaling in the Spinal Cord During Murine Autoimmune Neuroinflammation. Proc Natl Acad Sci USA (2020) 117:20088–99. doi: 10.1073/pnas.2006895117

  • CrossRef
  • Google Scholar

• 246

  BreuerJSchwabNSchneider-HohendorfTMarziniakMMohanHBhatiaUet al. Ultraviolet B Light Attenuates the Systemic Immune Response in Central Nervous System Autoimmunity. Ann Neurol (2014) 75:739–58. doi: 10.1002/ana.24165

  • CrossRef
  • Google Scholar

• 247

  HaasJKorporalMBalintBFritzschingBSchwarzAWildemannB. Glatiramer Acetate Improves Regulatory T-Cell Function by Expansion of Naive CD4(+)CD25(+)FOXP3(+)CD31(+) T-Cells in Patients With Multiple Sclerosis. J Neuroimmunol (2009) 216:113–7. doi: 10.1016/j.jneuroim.2009.06.011

  • CrossRef
  • Google Scholar

• 248

  MulsNDangHASindicCJMvan PeschV. Fingolimod Increases CD39-Expressing Regulatory T Cells in Multiple Sclerosis Patients. PloS One (2014) 9:e113025. doi: 10.1371/journal.pone.0113025

  • CrossRef
  • Google Scholar

• 249

  KorporalMHaasJBalintBFritzschingBSchwarzAMoellerSet al. Interferon Beta-Induced Restoration of Regulatory T-Cell Function in Multiple Sclerosis Is Prompted by an Increase in Newly Generated Naive Regulatory T Cells. Arch Neurol (2008) 65:1434–9. doi: 10.1001/archneur.65.11.1434

  • CrossRef
  • Google Scholar

• 250

  KornbergMDBhargavaPKimPMPutluriVSnowmanAMPutluriNet al. Dimethyl Fumarate Targets GAPDH and Aerobic Glycolysis to Modulate Immunity. Science (2018) 360:449–53. doi: 10.1126/science.aan4665

  • CrossRef
  • Google Scholar

• 251

  HaasJWürthweinCKorporal-KuhnkeMViehoeverAJariusSRuckTet al. Alemtuzumab in Multiple Sclerosis: Short- and Long-Term Effects of Immunodepletion on the Peripheral Treg Compartment. Front Immunol (2019) 10:1204. doi: 10.3389/fimmu.2019.01204

  • CrossRef
  • Google Scholar

• 252

  JamshidianAShaygannejadVPourazarAZarkesh-EsfahaniS-HGharagozlooM. Biased Treg/Th17 Balance Away From Regulatory Toward Inflammatory Phenotype in Relapsed Multiple Sclerosis and Its Correlation With Severity of Symptoms. J Neuroimmunol (2013) 262:106–12. doi: 10.1016/j.jneuroim.2013.06.007

  • CrossRef
  • Google Scholar

• 253

  FletcherJMLonerganRCostelloeLKinsellaKMoranBO’FarrellyCet al. CD39 ⁺ Foxp3 ⁺ Regulatory T Cells Suppress Pathogenic Th17 Cells and Are Impaired in Multiple Sclerosis. J Immunol (2009) 183:7602–10. doi: 10.4049/jimmunol.0901881

  • CrossRef
  • Google Scholar

• 254

  KornTReddyJGaoWBettelliEAwasthiAPetersenTRet al. Myelin-Specific Regulatory T Cells Accumulate in the CNS But Fail to Control Autoimmune Inflammation. Nat Med (2007) 13:423–31. doi: 10.1038/nm1564

  • CrossRef
  • Google Scholar

• 255

  JonesAPTrendSByrneSNFabis-PedriniMJGeldenhuysSNolanDet al. Altered Regulatory T-Cell Fractions and Helios Expression in Clinically Isolated Syndrome: Clues to the Development of Multiple Sclerosis. Clin Transl Immunol (2017) 6:e143. doi: 10.1038/cti.2017.18

  • CrossRef
  • Google Scholar

• 256

  KimuraKHohjohHFukuokaMSatoWOkiSTomiCet al. Circulating Exosomes Suppress the Induction of Regulatory T Cells via Let-7i in Multiple Sclerosis. Nat Commun (2018) 9:17. doi: 10.1038/s41467-017-02406-2

  • CrossRef
  • Google Scholar

• 257

  RojasMRestrepo-JiménezPMonsalveDMPachecoYAcosta-AmpudiaYRamírez-SantanaCet al. Molecular Mimicry and Autoimmunity. J Autoimmun (2018) 95:100–23. doi: 10.1016/j.jaut.2018.10.012

  • CrossRef
  • Google Scholar

• 258

  GettsDRChastainEMLTerryRLMillerSD. Virus Infection, Antiviral Immunity, and Autoimmunity. Immunol Rev (2013) 255:197–209. doi: 10.1111/imr.12091

  • CrossRef
  • Google Scholar

• 259

  PachecoYAcosta-AmpudiaYMonsalveDMChangCGershwinMEAnayaJ-M. Bystander Activation and Autoimmunity. J Autoimmun (2019) 103:102301. doi: 10.1016/j.jaut.2019.06.012

  • CrossRef
  • Google Scholar

• 260

  LosikoffPTMishraSTerryFGutierrezAArditoMTFastLet al. HCV Epitope, Homologous to Multiple Human Protein Sequences, Induces a Regulatory T Cell Response in Infected Patients. J Hepatol (2015) 62:48–55. doi: 10.1016/j.jhep.2014.08.026

  • CrossRef
  • Google Scholar

• 261

  DuarteJHZelenaySBergmanM-LMartinsACDemengeotJ. Natural Treg Cells Spontaneously Differentiate Into Pathogenic Helper Cells in Lymphopenic Conditions. Eur J Immunol (2009) 39:948–55. doi: 10.1002/eji.200839196

  • CrossRef
  • Google Scholar

• 262

  WarnerHBCarpRI. Multiple Sclerosis and Epstein-Barr Virus. Lancet (1981) 2:1290. doi: 10.1016/s0140-6736(81)91527-0

  • CrossRef
  • Google Scholar

• 263

  DobsonRKuhleJMiddeldorpJGiovannoniG. Epstein-Barr-Negative MS: A True Phenomenon? Neurol Neuroimmunol Neuroinflamm (2017) 4:e318. doi: 10.1212/NXI.0000000000000318

  • CrossRef
  • Google Scholar

• 264

  ThackerELMirzaeiFAscherioA. Infectious Mononucleosis and Risk for Multiple Sclerosis: A Meta-Analysis. Ann Neurol (2006) 59:499–503. doi: 10.1002/ana.20820

  • CrossRef
  • Google Scholar

• 265

  PakpoorJDisantoGGerberJEDobsonRMeierUCGiovannoniGet al. The Risk of Developing Multiple Sclerosis in Individuals Seronegative for Epstein-Barr Virus: A Meta-Analysis. Mult Scler (2013) 19:162–6. doi: 10.1177/1352458512449682

  • CrossRef
  • Google Scholar

• 266

  LevinLIMungerKLO’ReillyEJFalkKIAscherioA. Primary Infection With the Epstein-Barr Virus and Risk of Multiple Sclerosis. Ann Neurol (2010) 67:824–30. doi: 10.1002/ana.21978

  • CrossRef
  • Google Scholar

• 267

  LevinLIMungerKLRubertoneMVPeckCALennetteETSpiegelmanDet al. Temporal Relationship Between Elevation of Epstein-Barr Virus Antibody Titers and Initial Onset of Neurological Symptoms in Multiple Sclerosis. JAMA (2005) 293:2496–500. doi: 10.1001/jama.293.20.2496

  • CrossRef
  • Google Scholar

• 268

  LünemannJDTintoréMMessmerBStrowigTRoviraAPerkalHet al. Elevated Epstein-Barr Virus-Encoded Nuclear Antigen-1 Immune Responses Predict Conversion to Multiple Sclerosis. Ann Neurol (2010) 67:159–69. doi: 10.1002/ana.21886

  • CrossRef
  • Google Scholar

• 269

  FarrellRAAntonyDWallGRClarkDAFisnikuLSwantonJet al. Humoral Immune Response to EBV in Multiple Sclerosis Is Associated With Disease Activity on MRI. Neurology (2009) 73:32–8. doi: 10.1212/WNL.0b013e3181aa29fe

  • CrossRef
  • Google Scholar

• 270

  ZivadinovRCerzaNHagemeierJCarlEBadgettDRamasamyDPet al. Humoral Response to EBV Is Associated With Cortical Atrophy and Lesion Burden in Patients With MS. Neurol Neuroimmunol Neuroinflamm (2016) 3:e190. doi: 10.1212/NXI.0000000000000190

  • CrossRef
  • Google Scholar

• 271

  JakimovskiDRamanathanMWeinstock-GuttmanBBergslandNRamasamayDPCarlEet al. Higher EBV Response Is Associated With More Severe Gray Matter and Lesion Pathology in Relapsing Multiple Sclerosis Patients: A Case-Controlled Magnetization Transfer Ratio Study. Mult Scler (2020) 26:322–32. doi: 10.1177/1352458519828667

  • CrossRef
  • Google Scholar

• 272

  SerafiniBRosicarelliBFranciottaDMagliozziRReynoldsRCinquePet al. Dysregulated Epstein-Barr Virus Infection in the Multiple Sclerosis Brain. J Exp Med (2007) 204:2899–912. doi: 10.1084/jem.20071030

  • CrossRef
  • Google Scholar

• 273

  MagliozziRSerafiniBRosicarelliBChiappettaGVeroniCReynoldsRet al. B-Cell Enrichment and Epstein-Barr Virus Infection in Inflammatory Cortical Lesions in Secondary Progressive Multiple Sclerosis. J Neuropathol Exp Neurol (2013) 72:29–41. doi: 10.1097/NEN.0b013e31827bfc62

  • CrossRef
  • Google Scholar

• 274

  HassaniACorboyJRAl-SalamSKhanG. Epstein-Barr Virus Is Present in the Brain of Most Cases of Multiple Sclerosis and May Engage More Than Just B Cells. PloS One (2018) 13:e0192109. doi: 10.1371/journal.pone.0192109

  • CrossRef
  • Google Scholar

• 275

  Bar-OrAPenderMPKhannaRSteinmanLHartungH-PManiarTet al. Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies. Trends Mol Med (2020) 26:296–310. doi: 10.1016/j.molmed.2019.11.003

  • CrossRef
  • Google Scholar

• 276

  LünemannJDJelcićIRobertsSLutterottiATackenbergBMartinRet al. EBNA1-Specific T Cells From Patients With Multiple Sclerosis Cross React With Myelin Antigens and Co-Produce IFN-Gamma and IL-2. J Exp Med (2008) 205:1763–73. doi: 10.1084/jem.20072397

  • CrossRef
  • Google Scholar

• 277

  HolmøyTKvaleEØVartdalF. Cerebrospinal Fluid CD4+ T Cells From a Multiple Sclerosis Patient Cross-Recognize Epstein-Barr Virus and Myelin Basic Protein. J Neurovirol (2004) 10:278–83. doi: 10.1080/13550280490499524

  • CrossRef
  • Google Scholar

• 278

  TengvallKHuangJHellströmCKammerPBiströmMAyogluBet al. Molecular Mimicry Between Anoctamin 2 and Epstein-Barr Virus Nuclear Antigen 1 Associates With Multiple Sclerosis Risk. Proc Natl Acad Sci USA (2019) 116:16955–60. doi: 10.1073/pnas.1902623116

  • CrossRef
  • Google Scholar

• 279

  van NoortJMBajramovicJJPlompACvan StipdonkMJ. Mistaken Self, a Novel Model That Links Microbial Infections With Myelin-Directed Autoimmunity in Multiple Sclerosis. J Neuroimmunol (2000) 105:46–57. doi: 10.1016/s0165-5728(00)00181-8

  • CrossRef
  • Google Scholar

• 280

  LiRRezkAHealyLMMuirheadGPratAGommermanJLet al. MSSRF Canadian B Cells in MS Team. Cytokine-Defined B Cell Responses as Therapeutic Targets in Multiple Sclerosis. Front Immunol (2015) 6:626. doi: 10.3389/fimmu.2015.00626

  • CrossRef
  • Google Scholar

• 281

  D’AddarioMLibermannTAXuJAhmadAMenezesJ. Epstein-Barr Virus and Its Glycoprotein-350 Upregulate IL-6 in Human B-Lymphocytes via CD21, Involving Activation of NF-kappaB and Different Signaling Pathways. J Mol Biol (2001) 308:501–14. doi: 10.1006/jmbi.2001.4589

  • CrossRef
  • Google Scholar

• 282

  WangJJelcicIMühlenbruchLHaunerdingerVToussaintNCZhaoYet al. HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis. Cell (2020) 183:1264–81.e20. doi: 10.1016/j.cell.2020.09.054

  • CrossRef
  • Google Scholar

• 283

  ClottuASMathiasASailerAWSchluepMSeebachJDDu PasquierRet al. EBI2 Expression and Function: Robust in Memory Lymphocytes and Increased by Natalizumab in Multiple Sclerosis. Cell Rep (2017) 18:213–24. doi: 10.1016/j.celrep.2016.12.006

  • CrossRef
  • Google Scholar

• 284

  WankeFMoosSCroxfordALHeinenAPGräfSKaltBet al. EBI2 Is Highly Expressed in Multiple Sclerosis Lesions and Promotes Early CNS Migration of Encephalitogenic CD4 T Cells. Cell Rep (2017) 18:1270–84. doi: 10.1016/j.celrep.2017.01.020

  • CrossRef
  • Google Scholar

• 285

  RutkowskaAShimshekDRSailerAWDevKK. EBI2 Regulates Pro-Inflammatory Signalling and Cytokine Release in Astrocytes. Neuropharmacology (2018) 133:121–8. doi: 10.1016/j.neuropharm.2018.01.029

  • CrossRef
  • Google Scholar

• 286

  SerafiniBRosicarelliBMagliozziRStiglianoEAloisiF. Detection of Ectopic B-Cell Follicles With Germinal Centers in the Meninges of Patients With Secondary Progressive Multiple Sclerosis. Brain Pathol (2004) 14:164–74. doi: 10.1111/j.1750-3639.2004.tb00049.x

  • CrossRef
  • Google Scholar

• 287

  SutkowskiNPalkamaTCiurliCSekalyRPThorley-LawsonDAHuberBT. An Epstein-Barr Virus-Associated Superantigen. J Exp Med (1996) 184:971–80. doi: 10.1084/jem.184.3.971

  • CrossRef
  • Google Scholar

• 288

  AgarwalAKShahA. Menstrual-Linked Asthma. J Asthma (1997) 34:539–45. doi: 10.3109/02770909709055398

  • CrossRef
  • Google Scholar

• 289

  HummeSReisbachGFeederleRDelecluseH-JBoussetKHammerschmidtWet al. The EBV Nuclear Antigen 1 (EBNA1) Enhances B Cell Immortalization Several Thousandfold. Proc Natl Acad Sci USA (2003) 100:10989–94. doi: 10.1073/pnas.1832776100

  • CrossRef
  • Google Scholar

• 290

  PenderMPCsurhesPABurrowsJMBurrowsSR. Defective T-Cell Control of Epstein-Barr Virus Infection in Multiple Sclerosis. Clin Transl Immunol (2017) 6:e126. doi: 10.1038/cti.2016.87

  • CrossRef
  • Google Scholar

• 291

  MarrodanMAlessandroLFarezMFCorrealeJ. The Role of Infections in Multiple Sclerosis. Mult Scler (2019) 25:891–901. doi: 10.1177/1352458518823940

  • CrossRef
  • Google Scholar

• 292

  BrüttingCEmmerAKornhuberMStaegeMS. A Survey of Endogenous Retrovirus (ERV) Sequences in the Vicinity of Multiple Sclerosis (MS)-Associated Single Nucleotide Polymorphisms (SNPs). Mol Biol Rep (2016) 43:827–36. doi: 10.1007/s11033-016-4004-0

  • CrossRef
  • Google Scholar

• 293

  PerronHGenyCLaurentAMouriquandCPellatJPerretJet al. Leptomeningeal Cell Line From Multiple Sclerosis With Reverse Transcriptase Activity and Viral Particles. Res Virol (1989) 140:551–61. doi: 10.1016/s0923-2516(89)80141-4

  • CrossRef
  • Google Scholar

• 294

  GiffordRTristemM. The Evolution, Distribution and Diversity of Endogenous Retroviruses. Virus Genes (2003) 26:291–315. doi: 10.1023/a:1024455415443

  • CrossRef
  • Google Scholar

• 295

  MorandiETanasescuRTarlintonREConstantinescuCSZhangWTenchCet al. The Association Between Human Endogenous Retroviruses and Multiple Sclerosis: A Systematic Review and Meta-Analysis. PloS One (2017) 12:e0172415. doi: 10.1371/journal.pone.0172415

  • CrossRef
  • Google Scholar

• 296

  Garcia-MontojoMRodriguez-MartinERamos-MozoPOrtega-MadueñoIDominguez-MozoMIArias-LealAet al. Syncytin-1/HERV-W Envelope Is an Early Activation Marker of Leukocytes and Is Upregulated in Multiple Sclerosis Patients. Eur J Immunol (2020) 50:685–94. doi: 10.1002/eji.201948423

  • CrossRef
  • Google Scholar

• 297

  ChristensenTPetersenTThielSBrudekTEllermann-EriksenSMøller-LarsenA. Gene-Environment Interactions in Multiple Sclerosis: Innate and Adaptive Immune Responses to Human Endogenous Retrovirus and Herpesvirus Antigens and the Lectin Complement Activation Pathway. J Neuroimmunol (2007) 183:175–88. doi: 10.1016/j.jneuroim.2006.09.014

  • CrossRef
  • Google Scholar

• 298

  MameliGAstoneVArruGMarconiSLovatoLSerraCet al. Brains and Peripheral Blood Mononuclear Cells of Multiple Sclerosis (MS) Patients Hyperexpress MS-Associated Retrovirus/HERV-W Endogenous Retrovirus, But Not Human Herpesvirus 6. J Gen Virol (2007) 88:264–74. doi: 10.1099/vir.0.81890-0

  • CrossRef
  • Google Scholar

• 299

  SotgiuSMameliGSerraCZarboIRArruGDoleiA. Multiple Sclerosis-Associated Retrovirus and Progressive Disability of Multiple Sclerosis. Mult Scler (2010) 16:1248–51. doi: 10.1177/1352458510376956

  • CrossRef
  • Google Scholar

• 300

  DoleiASerraCMameliGPugliattiMSechiGCirottoMCet al. Multiple Sclerosis-Associated Retrovirus (MSRV) in Sardinian MS Patients. Neurology (2002) 58:471–3. doi: 10.1212/wnl.58.3.471

  • CrossRef
  • Google Scholar

• 301

  GrandiNTramontanoE. HERV Envelope Proteins: Physiological Role and Pathogenic Potential in Cancer and Autoimmunity. Front Microbiol (2018) 9:462. doi: 10.3389/fmicb.2018.00462

  • CrossRef
  • Google Scholar

• 302

  FirouziRRollandAMichelMJouvin-MarcheEHauwJJMalcus-VocansonCet al. Multiple Sclerosis-Associated Retrovirus Particles Cause T Lymphocyte-Dependent Death With Brain Hemorrhage in Humanized SCID Mice Model. J Neurovirol (2003) 9:79–93. doi: 10.1080/13550280390173328

  • CrossRef
  • Google Scholar

• 303

  RollandAJouvin-MarcheEViretCFaureMPerronHMarchePN. The Envelope Protein of a Human Endogenous Retrovirus-W Family Activates Innate Immunity Through CD14/TLR4 and Promotes Th1-Like Responses. J Immunol (2006) 176:7636–44. doi: 10.4049/jimmunol.176.12.7636

  • CrossRef
  • Google Scholar

• 304

  DuperrayABarbeDRaguenezGWekslerBBRomeroIACouraudP-Oet al. Inflammatory Response of Endothelial Cells to a Human Endogenous Retrovirus Associated With Multiple Sclerosis Is Mediated by TLR4. Int Immunol (2015) 27:545–53. doi: 10.1093/intimm/dxv025

  • CrossRef
  • Google Scholar

• 305

  PerronHDougier-ReynaudH-LLomparskiCPopaIFirouziRBertrandJ-Bet al. Human Endogenous Retrovirus Protein Activates Innate Immunity and Promotes Experimental Allergic Encephalomyelitis in Mice. PloS One (2013) 8:e80128. doi: 10.1371/journal.pone.0080128

  • CrossRef
  • Google Scholar

• 306

  de LucaVMartins HigaAMalta RomanoCPimenta MambriniGPeroniLATrivinho-StrixinoFet al. Cross-Reactivity Between Myelin Oligodendrocyte Glycoprotein and Human Endogenous Retrovirus W Protein: Nanotechnological Evidence for the Potential Trigger of Multiple Sclerosis. Micron (2019) 120:66–73. doi: 10.1016/j.micron.2019.02.005

  • CrossRef
  • Google Scholar

• 307

  KremerDSchichelTFörsterMTzekovaNBernardCvan der ValkPet al. Human Endogenous Retrovirus Type W Envelope Protein Inhibits Oligodendroglial Precursor Cell Differentiation. Ann Neurol (2013) 74:721–32. doi: 10.1002/ana.23970

  • CrossRef
  • Google Scholar

• 308

  KremerDGruchotJWeyersVOldemeierLGöttlePHealyLet al. pHERV-W Envelope Protein Fuels Microglial Cell-Dependent Damage of Myelinated Axons in Multiple Sclerosis. Proc Natl Acad Sci USA (2019) 116:15216–25. doi: 10.1073/pnas.1901283116

  • CrossRef
  • Google Scholar

• 309

  KremerDFörsterMSchichelTGöttlePHartungH-PPerronHet al. The Neutralizing Antibody GNbAC1 Abrogates HERV-W Envelope Protein-Mediated Oligodendroglial Maturation Blockade. Mult Scler (2015) 21:1200–3. doi: 10.1177/1352458514560926

  • CrossRef
  • Google Scholar

• 310

  MameliGPoddigheLMeiAUleriESotgiuSSerraCet al. Expression and Activation by Epstein Barr Virus of Human Endogenous Retroviruses-W in Blood Cells and Astrocytes: Inference for Multiple Sclerosis. PloS One (2012) 7:e44991. doi: 10.1371/journal.pone.0044991

  • CrossRef
  • Google Scholar

• 311

  LibbeyJECusickMFFujinamiRS. Role of Pathogens in Multiple Sclerosis. Int Rev Immunol (2014) 33:266–83. doi: 10.3109/08830185.2013.823422

  • CrossRef
  • Google Scholar

• 312

  TaiAKLukaJAblashiDHuberBT. HHV-6A Infection Induces Expression of HERV-K18-Encoded Superantigen. J Clin Virol (2009) 46:47–8. doi: 10.1016/j.jcv.2009.05.019

  • CrossRef
  • Google Scholar

• 313

  ChallonerPBSmithKTParkerJDMacLeodDLCoulterSNRoseTMet al. Plaque-Associated Expression of Human Herpesvirus 6 in Multiple Sclerosis. Proc Natl Acad Sci USA (1995) 92:7440–4. doi: 10.1073/pnas.92.16.7440

  • CrossRef
  • Google Scholar

• 314

  TarlintonREMartynovaERizvanovAAKhaiboullinaSVermaS. Role of Viruses in the Pathogenesis of Multiple Sclerosis. Viruses (2020) 12:E643. doi: 10.3390/v12060643

  • CrossRef
  • Google Scholar

• 315

  SoldanSSBertiRSalemNSecchieroPFlamandLCalabresiPAet al. Association of Human Herpes Virus 6 (HHV-6) With Multiple Sclerosis: Increased IgM Response to HHV-6 Early Antigen and Detection of Serum HHV-6 DNA. Nat Med (1997) 3:1394–7. doi: 10.1038/nm1297-1394

  • CrossRef
  • Google Scholar

• 316

  GoodmanADMockDJPowersJMBakerJVBlumbergBM. Human Herpesvirus 6 Genome and Antigen in Acute Multiple Sclerosis Lesions. J Infect Dis (2003) 187:1365–76. doi: 10.1086/368172

  • CrossRef
  • Google Scholar

• 317

  SandersVJFelisanSWaddellATourtellotteWW. Detection of Herpesviridae in Postmortem Multiple Sclerosis Brain Tissue and Controls by Polymerase Chain Reaction. J Neurovirol (1996) 2:249–58. doi: 10.3109/13550289609146888

  • CrossRef
  • Google Scholar

• 318

  LeibovitchECCarusoBHaSKSchindlerMKLeeNJLucianoNJet al. Herpesvirus Trigger Accelerates Neuroinflammation in a Nonhuman Primate Model of Multiple Sclerosis. Proc Natl Acad Sci USA (2018) 115:11292–7. doi: 10.1073/pnas.1811974115

  • CrossRef
  • Google Scholar

• 319

  HogestynJMMockDJMayer-ProschelM. Contributions of Neurotropic Human Herpesviruses Herpes Simplex Virus 1 and Human Herpesvirus 6 to Neurodegenerative Disease Pathology. Neural Regen Res (2018) 13:211–21. doi: 10.4103/1673-5374.226380

  • CrossRef
  • Google Scholar

• 320

  Tejada-SimonMVZangYCQHongJRiveraVMZhangJZ. Cross-Reactivity With Myelin Basic Protein and Human Herpesvirus-6 in Multiple Sclerosis. Ann Neurol (2003) 53:189–97. doi: 10.1002/ana.10425

  • CrossRef
  • Google Scholar

• 321

  CavalloS. Immune-Mediated Genesis of Multiple Sclerosis. J Transl Autoimmun (2020) 3:100039. doi: 10.1016/j.jtauto.2020.100039

  • CrossRef
  • Google Scholar

• 322

  BagosPGNikolopoulosGIoannidisA. Chlamydia Pneumoniae Infection and the Risk of Multiple Sclerosis: A Meta-Analysis. Mult Scler (2006) 12:397–411. doi: 10.1191/1352458506ms1291oa

  • CrossRef
  • Google Scholar

• 323

  DuCYaoS-YLjunggren-RoseASriramS. Chlamydia Pneumoniae Infection of the Central Nervous System Worsens Experimental Allergic Encephalitis. J Exp Med (2002) 196:1639–44. doi: 10.1084/jem.20020393

  • CrossRef
  • Google Scholar

• 324

  JaruvongvanichVSanguankeoAJaruvongvanichSUpalaS. Association Between Helicobacter Pylori Infection and Multiple Sclerosis: A Systematic Review and Meta-Analysis. Mult Scler Relat Disord (2016) 7:92–7. doi: 10.1016/j.msard.2016.03.013

  • CrossRef
  • Google Scholar

• 325

  PedriniMJFSeewannABennettKAWoodAJTJamesIBurtonJet al. Helicobacter Pylori Infection as a Protective Factor Against Multiple Sclerosis Risk in Females. J Neurol Neurosurg Psychiatry (2015) 86:603–7. doi: 10.1136/jnnp-2014-309495

  • CrossRef
  • Google Scholar

• 326

  CookKWCrooksJHussainKO’BrienKBraitchMKareemHet al. Helicobacter Pylori Infection Reduces Disease Severity in an Experimental Model of Multiple Sclerosis. Front Microbiol (2015) 6:52. doi: 10.3389/fmicb.2015.00052

  • CrossRef
  • Google Scholar

• 327

  McCuneALaneAMurrayLHarveyINairPDonovanJet al. Reduced Risk of Atopic Disorders in Adults With Helicobacter Pylori Infection. Eur J Gastroenterol Hepatol (2003) 15:637–40. doi: 10.1097/00042737-200306000-00010

  • CrossRef
  • Google Scholar

• 328

  LutherJDaveMHigginsPDRKaoJY. Association Between Helicobacter Pylori Infection and Inflammatory Bowel Disease: A Meta-Analysis and Systematic Review of the Literature. Inflamm Bowel Dis (2010) 16:1077–84. doi: 10.1002/ibd.21116

  • CrossRef
  • Google Scholar

• 329

  FlemingJOCookTD. Multiple Sclerosis and the Hygiene Hypothesis. Neurology (2006) 67:2085–6. doi: 10.1212/01.wnl.0000247663.40297.2d

  • CrossRef
  • Google Scholar

• 330

  WalshKPBradyMTFinlayCMBoonLMillsKHG. Infection With a Helminth Parasite Attenuates Autoimmunity Through TGF-Beta-Mediated Suppression of Th17 and Th1 Responses. J Immunol (2009) 183:1577–86. doi: 10.4049/jimmunol.0803803

  • CrossRef
  • Google Scholar

• 331

  SewellDQingZReinkeEElliotDWeinstockJSandorMet al. Immunomodulation of Experimental Autoimmune Encephalomyelitis by Helminth Ova Immunization. Int Immunol (2003) 15:59–69. doi: 10.1093/intimm/dxg012

  • CrossRef
  • Google Scholar

• 332

  La FlammeACRuddenklauKBäckströmBT. Schistosomiasis Decreases Central Nervous System Inflammation and Alters the Progression of Experimental Autoimmune Encephalomyelitis. Infect Immun (2003) 71:4996–5004. doi: 10.1128/IAI.71.9.4996-5004.2003

  • CrossRef
  • Google Scholar

• 333

  CorrealeJFarezM. Association Between Parasite Infection and Immune Responses in Multiple Sclerosis. Ann Neurol (2007) 61:97–108. doi: 10.1002/ana.21067

  • CrossRef
  • Google Scholar

• 334

  CorrealeJFarezMRazzitteG. Helminth Infections Associated With Multiple Sclerosis Induce Regulatory B Cells. Ann Neurol (2008) 64:187–99. doi: 10.1002/ana.21438

  • CrossRef
  • Google Scholar

• 335

  CorrealeJFarezMF. The Impact of Parasite Infections on the Course of Multiple Sclerosis. J Neuroimmunol (2011) 233:6–11. doi: 10.1016/j.jneuroim.2011.01.002

  • CrossRef
  • Google Scholar

• 336

  DouglasBOyesolaOCooperMMPoseyATait WojnoEGiacominPRet al. Immune System Investigation Using Parasitic Helminths. Annu Rev Immunol (2021) 39:639–65. doi: 10.1146/annurev-immunol-093019-122827

  • CrossRef
  • Google Scholar

• 337

  PenderMPCsurhesPASmithCBeagleyLHooperKDRajMet al. Epstein-Barr Virus-Specific Adoptive Immunotherapy for Progressive Multiple Sclerosis. Mult Scler (2014) 20:1541–4. doi: 10.1177/1352458514521888

  • CrossRef
  • Google Scholar

• 338

  HuntemannNRolfesLPawlitzkiMRuckTPfeufferSWiendlHet al. Failed, Interrupted, or Inconclusive Trials on Neuroprotective and Neuroregenerative Treatment Strategies in Multiple Sclerosis: Update 2015-2020. Drugs (2021) 81:1031–63. doi: 10.1007/s40265-021-01526-w

  • CrossRef
  • Google Scholar

• 339

  MadeiraABurgelinIPerronHCurtinFLangABFaucardR. MSRV Envelope Protein Is a Potent, Endogenous and Pathogenic Agonist of Human Toll-Like Receptor 4: Relevance of GNbAC1 in Multiple Sclerosis Treatment. J Neuroimmunol (2016) 291:29–38. doi: 10.1016/j.jneuroim.2015.12.006

  • CrossRef
  • Google Scholar

• 340

  CurtinFPerronHKrommingaAPorchetHLangAB. Preclinical and Early Clinical Development of GNbAC1, a Humanized IgG4 Monoclonal Antibody Targeting Endogenous Retroviral MSRV-Env Protein. MAbs (2015) 7:265–75. doi: 10.4161/19420862.2014.985021

  • CrossRef
  • Google Scholar

• 341

  CurtinFVidalVBernardCKrommingaALangABPorchetH. Serum Pharmacokinetics and Cerebrospinal Fluid Concentration Analysis of the New IgG4 Monoclonal Antibody GNbAC1 to Treat Multiple Sclerosis: A Phase 1 Study. MAbs (2016) 8:854–60. doi: 10.1080/19420862.2016.1168956

  • CrossRef
  • Google Scholar

• 342

  CurtinFLangABPerronHLaumonierMVidalVPorchetHCet al. GNbAC1, a Humanized Monoclonal Antibody Against the Envelope Protein of Multiple Sclerosis-Associated Endogenous Retrovirus: A First-in-Humans Randomized Clinical Study. Clin Ther (2012) 34:2268–78. doi: 10.1016/j.clinthera.2012.11.006

  • CrossRef
  • Google Scholar

• 343

  MaruszakHBrewBJGiovannoniGGoldJ. Could Antiretroviral Drugs be Effective in Multiple Sclerosis? A Case Report. Eur J Neurol (2011) 18:e110–111. doi: 10.1111/j.1468-1331.2011.03430.x

  • CrossRef
  • Google Scholar

• 344

  FlemingJHernandezGHartmanLMaksimovicJNaceSLawlerBet al. Safety and Efficacy of Helminth Treatment in Relapsing-Remitting Multiple Sclerosis: Results of the HINT 2 Clinical Trial. Mult Scler (2019) 25:81–91. doi: 10.1177/1352458517736377

  • CrossRef
  • Google Scholar

• 345

  RooksMGGarrettWS. Gut Microbiota, Metabolites and Host Immunity. Nat Rev Immunol (2016) 16:341–52. doi: 10.1038/nri.2016.42

  • CrossRef
  • Google Scholar

• 346

  ThaissCAZmoraNLevyMElinavE. The Microbiome and Innate Immunity. Nature (2016) 535:65–74. doi: 10.1038/nature18847

  • CrossRef
  • Google Scholar

• 347

  LiWDengYChuQZhangP. Gut Microbiome and Cancer Immunotherapy. Cancer Lett (2019) 447:41–7. doi: 10.1016/j.canlet.2019.01.015

  • CrossRef
  • Google Scholar

• 348

  De LucaFShoenfeldY. The Microbiome in Autoimmune Diseases. Clin Exp Immunol (2019) 195:74–85. doi: 10.1111/cei.13158

  • CrossRef
  • Google Scholar

• 349

  DickersonFSeveranceEYolkenR. The Microbiome, Immunity, and Schizophrenia and Bipolar Disorder. Brain Behav Immun (2017) 62:46–52. doi: 10.1016/j.bbi.2016.12.010

  • CrossRef
  • Google Scholar

• 350

  BarringtonWTLusisAJ. Atherosclerosis: Association Between the Gut Microbiome and Atherosclerosis. Nat Rev Cardiol (2017) 14:699–700. doi: 10.1038/nrcardio.2017.169

  • CrossRef
  • Google Scholar

• 351

  SprouseMLBatesNAFelixKMWuH-JJ. Impact of Gut Microbiota on Gut-Distal Autoimmunity: A Focus on T Cells. Immunology (2019) 156:305–18. doi: 10.1111/imm.13037

  • CrossRef
  • Google Scholar

• 352

  ScherJUAbramsonSB. The Microbiome and Rheumatoid Arthritis. Nat Rev Rheumatol (2011) 7:569–78. doi: 10.1038/nrrheum.2011.121

  • CrossRef
  • Google Scholar

• 353

  MathisDBenoistC. Microbiota and Autoimmune Disease: The Hosted Self. Cell Host Microbe (2011) 10:297–301. doi: 10.1016/j.chom.2011.09.007

  • CrossRef
  • Google Scholar

• 354

  OmenettiSPizarroTT. The Treg/Th17 Axis: A Dynamic Balance Regulated by the Gut Microbiome. Front Immunol (2015) 6:639. doi: 10.3389/fimmu.2015.00639

  • CrossRef
  • Google Scholar

• 355

  CebulaASewerynMRempalaGAPablaSSMcIndoeRADenningTLet al. Thymus-Derived Regulatory T Cells Contribute to Tolerance to Commensal Microbiota. Nature (2013) 497:258–62. doi: 10.1038/nature12079

  • CrossRef
  • Google Scholar

• 356

  AtarashiKTanoueTShimaTImaokaAKuwaharaTMomoseYet al. Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species. Science (2011) 331:337–41. doi: 10.1126/science.1198469

  • CrossRef
  • Google Scholar

• 357

  Ochoa-RepárazJMielcarzDWDitrioLEBurroughsARFoureauDMHaque-BegumSet al. Role of Gut Commensal Microflora in the Development of Experimental Autoimmune Encephalomyelitis. J Immunol (2009) 183:6041–50. doi: 10.4049/jimmunol.0900747

  • CrossRef
  • Google Scholar

• 358

  AtarashiKTanoueTOshimaKSudaWNaganoYNishikawaHet al. Treg Induction by a Rationally Selected Mixture of Clostridia Strains From the Human Microbiota. Nature (2013) 500:232–6. doi: 10.1038/nature12331

  • CrossRef
  • Google Scholar

• 359

  MortonAMSefikEUpadhyayRWeisslederRBenoistCMathisD. Endoscopic Photoconversion Reveals Unexpectedly Broad Leukocyte Trafficking to and From the Gut. Proc Natl Acad Sci USA (2014) 111:6696–701. doi: 10.1073/pnas.1405634111

  • CrossRef
  • Google Scholar

• 360

  EspluguesEHuberSGaglianiNHauserAETownTWanYYet al. Control of TH17 Cells Occurs in the Small Intestine. Nature (2011) 475:514–8. doi: 10.1038/nature10228

  • CrossRef
  • Google Scholar

• 361

  KadowakiASagaRLinYSatoWYamamuraT. Gut Microbiota-Dependent CCR9+CD4+ T Cells Are Altered in Secondary Progressive Multiple Sclerosis. Brain (2019) 142:916–31. doi: 10.1093/brain/awz012

  • CrossRef
  • Google Scholar

• 362

  TanoueTAtarashiKHondaK. Development and Maintenance of Intestinal Regulatory T Cells. Nat Rev Immunol (2016) 16:295–309. doi: 10.1038/nri.2016.36

  • CrossRef
  • Google Scholar

• 363

  ChaiJNPengYRengarajanSSolomonBDAiTLShenZet al. Helicobacter Species Are Potent Drivers of Colonic T Cell Responses in Homeostasis and Inflammation. Sci Immunol (2017) 2:eaal5068. doi: 10.1126/sciimmunol.aal5068

  • CrossRef
  • Google Scholar

• 364

  WhibleyNTucciAPowrieF. Regulatory T Cell Adaptation in the Intestine and Skin. Nat Immunol (2019) 20:386–96. doi: 10.1038/s41590-019-0351-z

  • CrossRef
  • Google Scholar

• 365

  BertoliniTBBiswasMTerhorstCDaniellHHerzogRWPiñerosAR. Role of Orally Induced Regulatory T Cells in Immunotherapy and Tolerance. Cell Immunol (2021) 359:104251. doi: 10.1016/j.cellimm.2020.104251

  • CrossRef
  • Google Scholar

• 366

  Arroyo HorneroRHamadICôrte-RealBKleinewietfeldM. The Impact of Dietary Components on Regulatory T Cells and Disease. Front Immunol (2020) 11:253. doi: 10.3389/fimmu.2020.00253

  • CrossRef
  • Google Scholar

• 367

  HaghikiaAJörgSDuschaABergJManzelAWaschbischAet al. Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. Immunity (2015) 43:817–29. doi: 10.1016/j.immuni.2015.09.007

  • CrossRef
  • Google Scholar

• 368

  MizunoMNotoDKagaNChibaAMiyakeS. The Dual Role of Short Fatty Acid Chains in the Pathogenesis of Autoimmune Disease Models. PloS One (2017) 12:e0173032. doi: 10.1371/journal.pone.0173032

  • CrossRef
  • Google Scholar

• 369

  ScheppachWSommerHKirchnerTPaganelliGMBartramPChristlSet al. Effect of Butyrate Enemas on the Colonic Mucosa in Distal Ulcerative Colitis. Gastroenterology (1992) 103:51–6. doi: 10.1016/0016-5085(92)91094-k

  • CrossRef
  • Google Scholar

• 370

  SunJFurioLMecheriRvan der DoesAMLundebergESaveanuLet al. Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed Under the Influence of the Gut Microbiota. Immunity (2015) 43:304–17. doi: 10.1016/j.immuni.2015.07.013

  • CrossRef
  • Google Scholar

• 371

  FurusawaYObataYFukudaSEndoTANakatoGTakahashiDet al. Commensal Microbe-Derived Butyrate Induces the Differentiation of Colonic Regulatory T Cells. Nature (2013) 504:446–50. doi: 10.1038/nature12721

  • CrossRef
  • Google Scholar

• 372

  SmithPMHowittMRPanikovNMichaudMGalliniCABohlooly-YMet al. The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis. Science (2013) 341:569–73. doi: 10.1126/science.1241165

  • CrossRef
  • Google Scholar

• 373

  MiyakeSKimSSudaWOshimaKNakamuraMMatsuokaTet al. Dysbiosis in the Gut Microbiota of Patients With Multiple Sclerosis, With a Striking Depletion of Species Belonging to Clostridia XIVa and IV Clusters. PloS One (2015) 10:e0137429. doi: 10.1371/journal.pone.0137429

  • CrossRef
  • Google Scholar

• 374

  MazmanianSKRoundJLKasperDL. A Microbial Symbiosis Factor Prevents Intestinal Inflammatory Disease. Nature (2008) 453:620–5. doi: 10.1038/nature07008

  • CrossRef
  • Google Scholar

• 375

  RoundJLMazmanianSK. Inducible Foxp3+ Regulatory T-Cell Development by a Commensal Bacterium of the Intestinal Microbiota. Proc Natl Acad Sci USA (2010) 107:12204–9. doi: 10.1073/pnas.0909122107

  • CrossRef
  • Google Scholar

• 376

  RoundJLLeeSMLiJTranGJabriBChatilaTAet al. The Toll-Like Receptor 2 Pathway Establishes Colonization by a Commensal of the Human Microbiota. Science (2011) 332:974–7. doi: 10.1126/science.1206095

  • CrossRef
  • Google Scholar

• 377

  ChuHKhosraviAKusumawardhaniIPKwonAHKVasconcelosACCunhaLDet al. Gene-Microbiota Interactions Contribute to the Pathogenesis of Inflammatory Bowel Disease. Science (2016) 352:1116–20. doi: 10.1126/science.aad9948

  • CrossRef
  • Google Scholar

• 378

  CekanaviciuteEYooBBRuniaTFDebeliusJWSinghSNelsonCAet al. Gut Bacteria From Multiple Sclerosis Patients Modulate Human T Cells and Exacerbate Symptoms in Mouse Models. Proc Natl Acad Sci USA (2017) 114:10713–8. doi: 10.1073/pnas.1711235114

  • CrossRef
  • Google Scholar

• 379

  JangiSGandhiRCoxLMLiNvon GlehnFYanRet al. Alterations of the Human Gut Microbiome in Multiple Sclerosis. Nat Commun (2016) 7:12015. doi: 10.1038/ncomms12015

  • CrossRef
  • Google Scholar

• 380

  SmitsHHEngeringAvan der KleijDde JongECSchipperKvan CapelTMMet al. Selective Probiotic Bacteria Induce IL-10-Producing Regulatory T Cells In Vitro by Modulating Dendritic Cell Function Through Dendritic Cell-Specific Intercellular Adhesion Molecule 3-Grabbing Nonintegrin. J Allergy Clin Immunol (2005) 115:1260–7. doi: 10.1016/j.jaci.2005.03.036

  • CrossRef
  • Google Scholar

• 381

  KwonH-KLeeC-GSoJ-SChaeC-SHwangJ-SSahooAet al. Generation of Regulatory Dendritic Cells and CD4+Foxp3+ T Cells by Probiotics Administration Suppresses Immune Disorders. Proc Natl Acad Sci USA (2010) 107:2159–64. doi: 10.1073/pnas.0904055107

  • CrossRef
  • Google Scholar

• 382

  Di GiacintoCMarinaroMSanchezMStroberWBoirivantM. Probiotics Ameliorate Recurrent Th1-Mediated Murine Colitis by Inducing IL-10 and IL-10-Dependent TGF-Beta-Bearing Regulatory Cells. J Immunol (2005) 174:3237–46. doi: 10.4049/jimmunol.174.6.3237

  • CrossRef
  • Google Scholar

• 383

  LavasaniSDzhambazovBNouriMFåkFBuskeSMolinGet al. A Novel Probiotic Mixture Exerts a Therapeutic Effect on Experimental Autoimmune Encephalomyelitis Mediated by IL-10 Producing Regulatory T Cells. PloS One (2010) 5:e9009. doi: 10.1371/journal.pone.0009009

  • CrossRef
  • Google Scholar

• 384

  TankouSKRegevKHealyBCTjonELaghiLCoxLMet al. A Probiotic Modulates the Microbiome and Immunity in Multiple Sclerosis. Ann Neurol (2018) 83:1147–61. doi: 10.1002/ana.25244

  • CrossRef
  • Google Scholar

• 385

  YanYRamananDRozenbergMMcGovernKRastelliDVijaykumarBet al. Interleukin-6 Produced by Enteric Neurons Regulates the Number and Phenotype of Microbe-Responsive Regulatory T Cells in the Gut. Immunity (2021) 54:499–513.e5. doi: 10.1016/j.immuni.2021.02.002

  • CrossRef
  • Google Scholar

• 386

  TerataniTMikamiYNakamotoNSuzukiTHaradaYOkabayashiKet al. The Liver-Brain-Gut Neural Arc Maintains the Treg Cell Niche in the Gut. Nature (2020) 585:591–6. doi: 10.1038/s41586-020-2425-3

  • CrossRef
  • Google Scholar

• 387

  McKinneyEFLyonsPACarrEJHollisJLJayneDRWWillcocksLCet al. A CD8+ T Cell Transcription Signature Predicts Prognosis in Autoimmune Disease. Nat Med (2010) 16:586–591, 1p following 591. doi: 10.1038/nm.2130

  • CrossRef
  • Google Scholar

• 388

  LeeJCLyonsPAMcKinneyEFSowerbyJMCarrEJBredinFet al. Gene Expression Profiling of CD8+ T Cells Predicts Prognosis in Patients With Crohn Disease and Ulcerative Colitis. J Clin Invest (2011) 121:4170–9. doi: 10.1172/JCI59255

  • CrossRef
  • Google Scholar

• 389

  YangZShenYOishiHMattesonELTianLGoronzyJJet al. Restoring Oxidant Signaling Suppresses Proarthritogenic T Cell Effector Functions in Rheumatoid Arthritis. Sci Transl Med (2016) 8:331ra38. doi: 10.1126/scitranslmed.aad7151

  • CrossRef
  • Google Scholar

• 390

  WagnerN-MBrandhorstGCzepluchFLankeitMEberleCHerzbergSet al. Circulating Regulatory T Cells Are Reduced in Obesity and May Identify Subjects at Increased Metabolic and Cardiovascular Risk: Regulatory T Cells and Obesity. Obesity (2013) 21:461–8. doi: 10.1002/oby.20087

  • CrossRef
  • Google Scholar

• 391

  PacellaIPiconeseS. Immunometabolic Checkpoints of Treg Dynamics: Adaptation to Microenvironmental Opportunities and Challenges. Front Immunol (2019) 10:1889. doi: 10.3389/fimmu.2019.01889

  • CrossRef
  • Google Scholar

• 392

  SchmidleithnerLThabetYSchönfeldEKöhneMSommerDAbdullahZet al. Enzymatic Activity of HPGD in Treg Cells Suppresses Tconv Cells to Maintain Adipose Tissue Homeostasis and Prevent Metabolic Dysfunction. Immunity (2019) 50:1232–48.e14. doi: 10.1016/j.immuni.2019.03.014

  • CrossRef
  • Google Scholar

• 393

  WuDHanJMYuXLamAJHoeppliREPesenackerAMet al. Characterization of Regulatory T Cells in Obese Omental Adipose Tissue in Humans. Eur J Immunol (2019) 49:336–47. doi: 10.1002/eji.201847570

  • CrossRef
  • Google Scholar

• 394

  LiMZhaoWWangYJinLJinGSunXet al. A Wave of Foxp3+ Regulatory T Cell Accumulation in the Neonatal Liver Plays Unique Roles in Maintaining Self-Tolerance. Cell Mol Immunol (2020) 17:507–18. doi: 10.1038/s41423-019-0246-9

  • CrossRef
  • Google Scholar

• 395

  KlingenbergRGerdesNBadeauRMGisteråAStrodthoffDKetelhuthDFJet al. Depletion of FOXP3+ Regulatory T Cells Promotes Hypercholesterolemia and Atherosclerosis. J Clin Invest (2013) 123:1323–34. doi: 10.1172/JCI63891

  • CrossRef
  • Google Scholar

• 396

  AndersenCJMurphyKEFernandezML. Impact of Obesity and Metabolic Syndrome on Immunity. Adv Nutr (2016) 7:66–75. doi: 10.3945/an.115.010207

  • CrossRef
  • Google Scholar

• 397

  FrydrychLMBianGO’LoneDEWardPADelanoMJ. Obesity and Type 2 Diabetes Mellitus Drive Immune Dysfunction, Infection Development, and Sepsis Mortality. J Leukoc Biol (2018) 104:525–34. doi: 10.1002/JLB.5VMR0118-021RR

  • CrossRef
  • Google Scholar

• 398

  GaneshanKChawlaA. Metabolic Regulation of Immune Responses. Annu Rev Immunol (2014) 32:609–34. doi: 10.1146/annurev-immunol-032713-120236

  • CrossRef
  • Google Scholar

• 399

  van der WindtGJWEvertsBChangC-HCurtisJDFreitasTCAmielEet al. Mitochondrial Respiratory Capacity Is a Critical Regulator of CD8+ T Cell Memory Development. Immunity (2012) 36:68–78. doi: 10.1016/j.immuni.2011.12.007

  • CrossRef
  • Google Scholar

• 400

  PearceELPearceEJ. Metabolic Pathways in Immune Cell Activation and Quiescence. Immunity (2013) 38:633–43. doi: 10.1016/j.immuni.2013.04.005

  • CrossRef
  • Google Scholar

• 401

  GeltinkRIKKyleRLPearceEL. Unraveling the Complex Interplay Between T Cell Metabolism and Function. Annu Rev Immunol (2018) 36:461–88. doi: 10.1146/annurev-immunol-042617-053019

  • CrossRef
  • Google Scholar

• 402

  SethRBSunLChenZJ. Antiviral Innate Immunity Pathways. Cell Res (2006) 16:141–7. doi: 10.1038/sj.cr.7310019

  • CrossRef
  • Google Scholar

• 403

  WaickmanATPowellJD. mTOR, Metabolism, and the Regulation of T-Cell Differentiation and Function. Immunol Rev (2012) 249:43–58. doi: 10.1111/j.1600-065X.2012.01152.x

  • CrossRef
  • Google Scholar

• 404

  WangRGreenDR. Metabolic Checkpoints in Activated T Cells. Nat Immunol (2012) 13:907–15. doi: 10.1038/ni.2386

  • CrossRef
  • Google Scholar

• 405

  SenaLALiSJairamanAPrakriyaMEzpondaTHildemanDAet al. Mitochondria Are Required for Antigen-Specific T Cell Activation Through Reactive Oxygen Species Signaling. Immunity (2013) 38:225–36. doi: 10.1016/j.immuni.2012.10.020

  • CrossRef
  • Google Scholar

• 406

  PearceEL. Metabolism in T Cell Activation and Differentiation. Curr Opin Immunol (2010) 22:314–20. doi: 10.1016/j.coi.2010.01.018

  • CrossRef
  • Google Scholar

• 407

  PearceELWalshMCCejasPJHarmsGMShenHWangL-Set al. Enhancing CD8 T-Cell Memory by Modulating Fatty Acid Metabolism. Nature (2009) 460:103–7. doi: 10.1038/nature08097

  • CrossRef
  • Google Scholar

• 408

  van der WindtGJWPearceEL. Metabolic Switching and Fuel Choice During T-Cell Differentiation and Memory Development. Immunol Rev (2012) 249:27–42. doi: 10.1111/j.1600-065X.2012.01150.x

  • CrossRef
  • Google Scholar

• 409

  WangRDillonCPShiLZMilastaSCarterRFinkelsteinDet al. The Transcription Factor Myc Controls Metabolic Reprogramming Upon T Lymphocyte Activation. Immunity (2011) 35:871–82. doi: 10.1016/j.immuni.2011.09.021

  • CrossRef
  • Google Scholar

• 410

  LoY-CLeeC-FPowellJD. Insight Into the Role of mTOR and Metabolism in T Cells Reveals New Potential Approaches to Preventing Graft Rejection. Curr Opin Organ Transplant (2014) 19:363–71. doi: 10.1097/MOT.0000000000000098

  • CrossRef
  • Google Scholar

• 411

  De RosaVGalganiMPorcelliniAColamatteoASantopaoloMZuchegnaCet al. Glycolysis Controls the Induction of Human Regulatory T Cells by Modulating the Expression of FOXP3 Exon 2 Splicing Variants. Nat Immunol (2015) 16:1174–84. doi: 10.1038/ni.3269

  • CrossRef
  • Google Scholar

• 412

  GerrietsVAKishtonRJJohnsonMOCohenSSiskaPJNicholsAGet al. Foxp3 and Toll-Like Receptor Signaling Balance Treg Cell Anabolic Metabolism for Suppression. Nat Immunol (2016) 17:1459–66. doi: 10.1038/ni.3577

  • CrossRef
  • Google Scholar

• 413

  ProcacciniCCarboneFDi SilvestreDBrambillaFDe RosaVGalganiMet al. The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements. Immunity (2016) 44:406–21. doi: 10.1016/j.immuni.2016.01.028

  • CrossRef
  • Google Scholar

• 414

  LiLLiuXSandersKLEdwardsJLYeJSiFet al. TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy. Cell Metab (2019) 29:103–23.e5. doi: 10.1016/j.cmet.2018.09.020

  • CrossRef
  • Google Scholar

• 415

  HeNFanWHenriquezBYuRTAtkinsARLiddleCet al. Metabolic Control of Regulatory T Cell (Treg) Survival and Function by Lkb1. Proc Natl Acad Sci USA (2017) 114:12542–7. doi: 10.1073/pnas.1715363114

  • CrossRef
  • Google Scholar

• 416

  YangKBlancoDBNealeGVogelPAvilaJClishCBet al. Homeostatic Control of Metabolic and Functional Fitness of Treg Cells by LKB1 Signalling. Nature (2017) 548:602–6. doi: 10.1038/nature23665

  • CrossRef
  • Google Scholar

• 417

  WeinbergSESingerBDSteinertEMMartinezCAMehtaMMMartínez-ReyesIet al. Mitochondrial Complex III Is Essential for Suppressive Function of Regulatory T Cells. Nature (2019) 565:495–9. doi: 10.1038/s41586-018-0846-z

  • CrossRef
  • Google Scholar

• 418

  MichalekRDGerrietsVAJacobsSRMacintyreANMacIverNJMasonEFet al. Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets. J Immunol (2011) 186:3299–303. doi: 10.4049/jimmunol.1003613

  • CrossRef
  • Google Scholar

• 419

  XieMZhangDDyckJRBLiYZhangHMorishimaMet al. A Pivotal Role for Endogenous TGF-Beta-Activated Kinase-1 in the LKB1/AMP-Activated Protein Kinase Energy-Sensor Pathway. Proc Natl Acad Sci USA (2006) 103:17378–83. doi: 10.1073/pnas.0604708103

  • CrossRef
  • Google Scholar

• 420

  GualdoniGAMayerKAGöschlLBoucheronNEllmeierWZlabingerGJ. The AMP Analog AICAR Modulates the Treg/Th17 Axis Through Enhancement of Fatty Acid Oxidation. FASEB J (2016) 30:3800–9. doi: 10.1096/fj.201600522R

  • CrossRef
  • Google Scholar

• 421

  BeierUHAngelinAAkimovaTWangLLiuYXiaoHet al. Essential Role of Mitochondrial Energy Metabolism in Foxp3⁺ T-Regulatory Cell Function and Allograft Survival. FASEB J (2015) 29:2315–26. doi: 10.1096/fj.14-268409

  • CrossRef
  • Google Scholar

• 422

  ChapmanNMZengHNguyenT-LMWangYVogelPDhunganaYet al. mTOR Coordinates Transcriptional Programs and Mitochondrial Metabolism of Activated Treg Subsets to Protect Tissue Homeostasis. Nat Commun (2018) 9:2095. doi: 10.1038/s41467-018-04392-5

  • CrossRef
  • Google Scholar

• 423

  KempkesRWMJoostenIKoenenHJPMHeX. Metabolic Pathways Involved in Regulatory T Cell Functionality. Front Immunol (2019) 10:2839. doi: 10.3389/fimmu.2019.02839

  • CrossRef
  • Google Scholar

• 424

  CluxtonDPetrascaAMoranBFletcherJM. Differential Regulation of Human Treg and Th17 Cells by Fatty Acid Synthesis and Glycolysis. Front Immunol (2019) 10:115. doi: 10.3389/fimmu.2019.00115

  • CrossRef
  • Google Scholar

• 425

  ZengHYangKCloerCNealeGVogelPChiH. mTORC1 Couples Immune Signals and Metabolic Programming to Establish T(reg)-Cell Function. Nature (2013) 499:485–90. doi: 10.1038/nature12297

  • CrossRef
  • Google Scholar

• 426

  ThurnherMGruenbacherG. T Lymphocyte Regulation by Mevalonate Metabolism. Sci Signal (2015) 8:re4. doi: 10.1126/scisignal.2005970

  • CrossRef
  • Google Scholar

• 427

  HuynhADuPageMPriyadharshiniBSagePTQuirosJBorgesCMet al. Control of PI(3) Kinase in Treg Cells Maintains Homeostasis and Lineage Stability. Nat Immunol (2015) 16:188–96. doi: 10.1038/ni.3077

  • CrossRef
  • Google Scholar

• 428

  TurnerMSKaneLPMorelPA. Dominant Role of Antigen Dose in CD4+Foxp3+ Regulatory T Cell Induction and Expansion. J Immunol (2009) 183:4895–903. doi: 10.4049/jimmunol.0901459

  • CrossRef
  • Google Scholar

• 429

  MiskaJLee-ChangCRashidiAMuroskiMEChangALLopez-RosasAet al. HIF-1α Is a Metabolic Switch Between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma. Cell Rep (2019) 27:226–37.e4. doi: 10.1016/j.celrep.2019.03.029

  • CrossRef
  • Google Scholar

• 430

  KishoreMCheungKCPFuHBonacinaFWangGCoeDet al. Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis. Immunity (2017) 47:875–89.e10. doi: 10.1016/j.immuni.2017.10.017

  • CrossRef
  • Google Scholar

• 431

  YeYChenYSunJZhangHMengYLiWet al. Hyperglycemia Suppresses the Regulatory Effect of Hypoxia-Inducible Factor-1α in Pulmonary Aspergillus Fumigatus Infection. Pathog Dis (2020) 78:ftaa038. doi: 10.1093/femspd/ftaa038

  • CrossRef
  • Google Scholar

• 432

  ShiLZWangRHuangGVogelPNealeGGreenDRet al. HIF1alpha-Dependent Glycolytic Pathway Orchestrates a Metabolic Checkpoint for the Differentiation of TH17 and Treg Cells. J Exp Med (2011) 208:1367–76. doi: 10.1084/jem.20110278

  • CrossRef
  • Google Scholar

• 433

  DangEVBarbiJYangH-YJinasenaDYuHZhengYet al. Control of TH17/Treg Balance by Hypoxia-Inducible Factor 1. Cell (2011) 146:772–84. doi: 10.1016/j.cell.2011.07.033

  • CrossRef
  • Google Scholar

• 434

  Pålsson-McDermottEMO’NeillLAJ. Targeting Immunometabolism as an Anti-Inflammatory Strategy. Cell Res (2020) 30:300–14. doi: 10.1038/s41422-020-0291-z

  • CrossRef
  • Google Scholar

• 435

  ZarroukMFinlayDKForetzMViolletBCantrellDA. Adenosine-Mono-Phosphate-Activated Protein Kinase-Independent Effects of Metformin in T Cells. PloS One (2014) 9:e106710. doi: 10.1371/journal.pone.0106710

  • CrossRef
  • Google Scholar

• 436

  PalmaCLa RoccaCGigantinoVAquinoGPiccaroGDi SilvestreDet al. Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection From Tuberculosis. Cell Metab (2021) 33:300–18.e12. doi: 10.1016/j.cmet.2020.12.016

  • CrossRef
  • Google Scholar

• 437

  LiYWeiCXuHJiaJWeiZGuoRet al. The Immunoregulation of Th17 in Host Against Intracellular Bacterial Infection. Mediators Inflamm (2018) 2018:6587296. doi: 10.1155/2018/6587296

  • CrossRef
  • Google Scholar

• 438

  ArpaiaNCampbellCFanXDikiySvan der VeekenJdeRoosPet al. Metabolites Produced by Commensal Bacteria Promote Peripheral Regulatory T-Cell Generation. Nature (2013) 504:451–5. doi: 10.1038/nature12726

  • CrossRef
  • Google Scholar

• 439

  DuschaAGiseviusBHirschbergSYissacharNStanglGIEilersEet al. Propionic Acid Shapes the Multiple Sclerosis Disease Course by an Immunomodulatory Mechanism. Cell (2020) 180:1067–80.e16. doi: 10.1016/j.cell.2020.02.035

  • CrossRef
  • Google Scholar