The immunobiology and therapeutic potential of regulatory T cells in autoimmune diseases and allergic diseases

Autoimmune and allergic diseases represent two major categories of immune-mediated disorders that collectively impose a significant global health burden. Although driven by distinct triggers—aberrant responses against self-antigens in autoimmunity and hypersensitivity to innocuous environmental antigens in allergy—both classes of disease are fundamentally rooted in a failure of immunological tolerance. At the center of this regulatory failure lies the dysfunction of regulatory T cells (Tregs) which are the master orchestrators of peripheral tolerance, actively suppressing effector immune responses through the secretion of inhibitory cytokines and contact-dependent inhibition. In both autoimmune and allergic conditions, defects in Treg number, stability, or suppressive function permit the uncontrolled expansion of autoreactive lymphocytes in autoimmunity, while in allergic diseases, it fails to constrain the T helper 2 (Th2) cell-mediated pathways that drive pathology. Despite the well-established role of Tregs in each disease category, research often proceeds in parallel, leaving a critical knowledge gap regarding the convergent mechanisms of Treg failure across these interconnected pathologies. A unified understanding of how factors such as genetic predispositions and environmental influences cohesively impact Treg function remains underdeveloped. This review addresses this gap by providing a comprehensive synthesis of Treg immunobiology, with a specific emphasis on the convergent pathways that underpin their dysfunction in both autoimmune and allergic diseases. By elucidating the shared principles of Treg-mediated immune dysregulation, this review aims to provide a robust conceptual framework to accelerate the development of next-generation therapies capable of restoring tolerance across this broad spectrum of disorders.

1 Introduction

Autoimmune diseases and allergic diseases represent two major categories of immune-mediated disorders that collectively affect millions worldwide, imposing significant burdens on healthcare systems and quality of life (1). Autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, and type 1 diabetes, arise from aberrant immune responses targeting self-antigens, leading to chronic inflammation and tissue damage (2), allergic diseases, including asthma, atopic dermatitis, and food allergies, involve hypersensitivity reactions to innocuous environmental antigens, often mediated by type 2 immune pathways (3). Despite these apparent differences, both conditions share a common underlying mechanism: dysregulation of immune tolerance, where the immune system fails to appropriately suppress harmful responses (4, 5).

Central to this immune homeostasis are Tregs, a specialized subset of CD4⁺ T lymphocytes characterized by the expression of the transcription factor Foxp3, which orchestrate peripheral tolerance by suppressing effector T cell activation, cytokine production, and antigen-presenting cell function (6). Tregs exert their suppressive effects through multiple mechanisms, including the secretion of anti-inflammatory cytokines such as IL-10 and TGF-β, direct cell-cell contact via CTLA-4, and modulation of dendritic cell maturation. In healthy individuals, Tregs maintain a delicate balance, preventing autoimmunity by tolerizing self-reactive T cells and averting allergies by dampening responses to allergens. In autoimmune diseases, Treg dysfunction—manifested as reduced numbers, impaired suppressive capacity, or defective trafficking to inflamed tissues—contributes to the breakdown of self-tolerance, allowing autoreactive T and B cells to proliferate unchecked (7). Similarly, in allergic diseases, diminished Treg activity or altered Treg subsets fail to curb Th2-skewed responses, resulting in excessive IgE production, mast cell degranulation, and eosinophilic inflammation (8). A key commonality between these disorders lies in the shared role of Tregs in enforcing tolerance: both involve a failure of Treg-mediated suppression, albeit against distinct antigen types—self-antigens in autoimmunity and exogenous allergens in allergies (9). This overlap is further evidenced by genetic associations, such as polymorphisms in FoxP3 or IL-10 genes, which predispose individuals to both autoimmune and allergic pathologies, highlighting a unified immunoregulatory defect (10). Despite these parallels, research into the shared immunobiological roles of Tregs across autoimmune and allergic diseases remains notably sparse, with most studies addressing these conditions in isolation rather than exploring integrated mechanisms, such as overlapping genetic predispositions (e.g., FoxP3 polymorphisms) or environmental modulators that influence Treg stability in both contexts. This knowledge gap underscores a critical opportunity for deeper investigation, as elucidating common Treg pathways could unveil novel insights into immune homeostasis and disease interconnection.

This review explores the immunobiology of Tregs, emphasizing their shared mechanisms in autoimmune and allergic diseases, and discusses emerging therapeutic avenues to harness Tregs for disease modulation. By bridging the research void on Treg functions in autoimmune and allergic diseases, this review aims to propel advancements in targeted Treg-based therapies, fostering innovative strategies that could simultaneously address the shared immunoregulatory deficits and improve clinical outcomes across these interrelated spectra of immune pathology.

2 Immunobiology of Tregs

Tregs represent a specialized lineage of CD4⁺ T cells indispensable for maintaining immune homeostasis and peripheral self-tolerance, thereby preventing autoimmune and allergic pathologies. Their identity and potent immunosuppressive functions are governed by the master transcription factor FoxP3. Phenotypically, Tregs are characterized by high-level expression of the interleukin-2 receptor α-chain (CD25) and low-level expression of the IL-7 receptor α-chain (CD127), a profile that reflects their dependence on IL-2 for survival and lineage stability.

The Treg compartment is broadly divided into two major subsets based on developmental origin: thymic Tregs (tTregs), which arise in the thymus and are also known as natural Tregs (nTregs), and peripherally derived Tregs (pTregs), which differentiate from naïve CD4⁺ T cells in extrathymic tissues (11–14). As depicted in Figure 1, these subsets have distinct yet complementary roles. tTregs are crucial for enforcing central tolerance to self-antigens. In contrast, pTregs primarily establish tissue residency, where they are pivotal for orchestrating organ-specific homeostasis and modulating local immune responses to non-self antigens, such as commensal microbiota and allergens (11, 12). For instance, pTreg differentiation in the intestine and lungs can be driven by microbial metabolites or by cytokines like transforming growth factor-β (TGF-β) and retinoic acid (15, 16). Intestinal pTregs, in particular, provide critical protection against food allergies (17, 18). A key distinction between these subsets lies in their T cell receptor (TCR) repertoires; pTregs exhibit greater diversity, enabling them to recognize a broader array of foreign antigens and effectively engage with peripheral pathogens and allergens (19).

Figure 1

Figure 1. Origin and development of Tregs. Treg cells originate in the thymus, known as natural Tregs (nTregs), or develop in the periphery from naive CD4⁺ T cells into induced Tregs (iTregs). Tolerance to self-antigens is mediated by nTregs, whereas tolerance at mucosal surfaces is maintained by iTregs that develop in peripheral tissues. Stimulation with TGF-β and retinoic acid, as well as exposure to food allergens, promote differentiation of iTregs in the gut. In the lungs, iTregs are activated by airborne allergens and by TGF-β and retinoic acid released by alveolar macrophages. iTregs in the skin are activated by contact with skin allergens and by TGF-β produced by dendritic cells (DCs).

Irrespective of their origin, Tregs suppress effector T cell (Teff) responses through a sophisticated and multifaceted array of mechanisms, encompassing both soluble mediators and direct cell-cell interactions (Figure 2). Key soluble factors secreted by Tregs include classical immunosuppressive cytokines such as interleukin-10 (IL-10), which inhibits Teff activation, as well as TGF-β and IL-35, which promote Treg differentiation and function. Additionally, Tregs can induce Teff apoptosis through the release of cytotoxic molecules such as granzymes A and B (20–23); intriguingly, granzyme B-expressing Tregs may themselves be more susceptible to apoptosis, potentially serving as a self-regulatory feedback mechanism to prevent excessive tissue damage (24). Cell-cell interactions, meanwhile, engage an array of immune checkpoints, encompassing cytotoxic T lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), CD73, CD39, and the interleukin-33 receptor (ST2) (25), as depicted in Figure 2. The transcription factor Helios bolsters Treg suppressive efficacy and resilience, especially under inflammatory duress (26, 27). Mechanistically, CTLA-4 on Tregs ligates B7 molecules (CD80/CD86) on antigen-presenting cells (APCs) and Teff cells, thereby dampening Teff proliferation and activation (28). LAG-3 engages major histocompatibility complex class II on APCs to propagate inhibitory signals (29, 30). Tregs also harness membrane-bound ectonucleotidases CD39 and CD73, which catalyze the sequential degradation of extracellular adenosine triphosphate (ATP) to adenosine, a potent immunosuppressant (31). Adenosine ligation to Teff receptors curtails their expansion and attenuates proinflammatory cytokine elaboration; however, adenosine accrual exerts nuanced repercussions on Tregs themselves, with protracted or elevated exposure potentially eroding their suppressive vigor (31). Under inflammatory stress, the transcription factor Helios enhances Treg stability and suppressive capacity (32), while ST2, the receptor for IL-33, acts as an “activation sensor” on tissue-resident Tregs, responding to local inflammatory signals to augment their function (33).

Figure 2

Figure 2. Treg cells suppress immune responses through multiple mechanisms. Tregs regulate both innate and adaptive immune responses through a variety of pathways, such as cytolysis (granzyme), metabolic disruption (CD25, CD39, and CD73), cell-to-cell contact (CTLA-4 and LAG-3), and secretion of inhibitory cytokines (TGF-β, IL-10, and IL-35). ATP, adenosine triphosphate; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DC, dendritic cell; LAG-3, lymphocyte-activation gene 3; Teff, effector T cell; TGF-β, transforming growth factor β; Treg, regulatory T cell.

The clinical and physiological import of this suppressive versatility crystallizes in the exquisite equilibrium Tregs uphold with diverse Teff subsets, whose perturbation frequently precipitates immune pathologies. Autoimmune conditions, for example, are often propelled by Th1-mediated surges in IL-2 and interferon-γ (IFN-γ), whereas allergic manifestations are chiefly sustained by Th2-driven IL-4 and IL-5 (34). Nowhere is this interplay more salient than in the Treg–Th17 axis, where both lineages derive from shared naïve CD4⁺ progenitors, their trajectories sculpted by the prevailing cytokine milieu. In disorders like inflammatory bowel disease (IBD), a proinflammatory niche skews differentiation toward pathogenic Th17 cells, curtailing Treg emergence and eroding the homeostatic Treg/Th17 balance. This disequilibrium is typified by diminished Treg/Th17 ratios in circulation and lesional tissues, culminating in the hallmark chronic inflammation of such ailments (35).

3 Plasticity and epigenetic regulation of regulatory T cells

Tregs exhibit remarkable plasticity, enabling them to adapt their cytokine and chemokine profiles to modulate inflammatory responses through interactions with diverse immune cell subsets. This plasticity allows Tregs to tailor their suppressive functions to specific immunological contexts. For instance, in the Peyer’s patches of the murine intestine, interleukin-6 (IL-6) and IL-21 induce Tregs to differentiate into follicular regulatory T cells (Tfr), which resemble follicular T helper (Tfh) cells (36–38). These Tfr cells migrate to germinal centers, where they promote germinal center formation while suppressing Tfh-driven B cell activation and antibody production (39–41). Similarly, Tregs co-expressing the T-box transcription factor T-bet alongside FoxP3 give rise to Th1-like Tregs, which secrete interferon-γ (IFN-γ) to curb excessive type 2 immune responses in allergic conditions while retaining their suppressive capacity (42–45). The plasticity of Tregs is particularly critical in autoimmune diseases, where Tregs acquire specialized properties to restrain specific T helper (Th) cell subsets (46). However, aberrant Treg plasticity can contribute to immune dysregulation. For example, in type 1 diabetes (T1D), an elevated frequency of IFN-γ⁺FoxP3⁺ (Th1-like) Tregs has been observed in peripheral blood, accompanied by diminished suppressive function and a proinflammatory phenotype (Table 1) (47). In chronic inflammatory settings, such as allergic diseases, Tregs can shift from a suppressive to a proinflammatory state. Gut-resident Tregs expressing RAR-related orphan receptor gamma t (RORγt), termed Th17-like Tregs, typically mitigate food allergies. However, in the pulmonary microenvironment, these cells may paradoxically exacerbate allergic asthma by producing IL-17 (48, 49, 51, 53). Additionally, Tregs co-expressing FoxP3, GATA-binding protein 3 (GATA3), and the chemotactic receptor-homolog expressed on Th2 cells (CRTH2) recruit type 2 innate lymphoid cells (ILC2s) to the lungs, where the secretion of IL-4, IL-5, and IL-13 by these Th2-like Tregs aggravates allergic asthma and food allergies (50, 51, 54–56). Prolonged exposure to chronic inflammation can lead to the loss of FoxP3 expression, resulting in the emergence of ex-Tregs—former Tregs that relinquish their suppressive function and adopt a conventional effector T cell phenotype, thereby contributing to pathogenic immune responses and amplifying allergic inflammation (52).

Table 1

Table 1. Treg subtypes.

Epigenetic mechanisms, including DNA methylation and histone modifications, are pivotal in governing Treg plasticity at key genomic loci. Natural Tregs (nTregs) are distinguished from induced Tregs (iTregs) by pronounced DNA hypomethylation at the FoxP3 promoter and enhancer regions, notably the Treg-specific demethylated region (TSDR), also known as conserved noncoding sequence 2 (CNS2) (57, 58). The maintenance of DNA methylation by DNA methyltransferase 1 (DNMT1) and Ten-Eleven Translocation (TET) enzymes is critical for stabilizing FoxP3 expression in nTregs within the thymus; disruption of these enzymes leads to reduced Treg numbers and compromised suppressive function (59). Thus, a characteristic hypomethylation pattern, coupled with sustained methylation maintenance, is essential for preserving nTreg lineage identity and functionality. Beyond methylation, the FoxP3 locus undergoes histone acetylation during Treg development, with histone acetyltransferases (HATs) promoting stable FoxP3 expression (60, 61). Chronic inflammatory environments potently drive epigenetic alterations, directly influencing Treg plasticity. Loss of TET or HAT activity, triggered by infection or metabolic shifts, can precipitate FoxP3 downregulation, prompting Tregs to adopt a Th17-like phenotype (61). Sustained IL-6 signaling, for instance, enhances DNMT1-mediated DNA methylation and histone deacetylase (HDAC) activity, further promoting FoxP3 loss (62). The extensive epigenetic regulation involved in Treg plasticity presents promising therapeutic opportunities, and targeting these epigenetic mechanisms may modulate Treg function in allergic diseases.

4 Regulatory T cells in autoimmune and allergic diseases

4.1 Regulatory T cells in autoimmune diseases

Regulatory T cells (Tregs) are essential for maintaining immune tolerance by balancing responses to foreign and self-antigens and preventing excessive inflammation that would otherwise cause tissue damage or fatal immunopathology (63). The critical role of the transcription factor FoxP3 in Treg development and function was first demonstrated in scurfy mice and later in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, in which loss-of-function mutations in FoxP3 result in a profound deficiency of functional Tregs, leading to uncontrolled effector T-cell (Teff) activation, multiorgan inflammation, autoantibody production, and early mortality (see Figure 3) (64, 65). Similar immunodysregulation occurs with defects in other key Treg-associated molecules, such as the IL-2 receptor α-chain (CD25) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), with CD25 mutations causing severe autoimmunity and CTLA-4 haploinsufficiency predisposing individuals to a broad spectrum of autoimmune disorders (66, 67). The indispensable role of Tregs in restraining autoimmunity has been further validated in classical experiments using immunodeficient nude mice: reconstitution with CD4⁺ T cells depleted of the CD25⁺ subset induces various organ-specific autoimmune diseases, whereas transfer of the CD4⁺CD25⁺ fraction prevents disease onset (68–70).

Figure 3

Figure 3. Role of regulatory T cells (Tregs) in autoimmune diseases therapy. Negative selection occurs in the medulla when the TCR of a thymocyte binds with high affinity to a peptide-MHC ligand on medullary thymic epithelial cells, resulting in a self-reactive and subsequent apoptotic cell death. As this process is not always effective, some self-reactive T cells evade elimination and enter the periphery possibly causing autoimmune diseases. High-affinity tissue-restricted binding of MHCII/TCR and subsequent IL-2 signaling leads to upregulation of FoxP3 and CD25. Low-affinity binding results in naive CD4⁺T cells. These naive CD4⁺ T cells may develop in the periphery to iTregs. Tregs play a role in suppressing immune responses directed against both self and non-self-antigens.

Collectively, these findings establish Tregs as central regulators of immune homeostasis and underscore the inadequacy of current autoimmune disease treatments, which remain largely palliative and rely on non-specific systemic immunosuppression rather than correction of underlying immune dysregulation (71). Advances in mechanistic understanding have prompted the development of more targeted therapeutic strategies—such as autoantigen-specific immunomodulation, Treg adoptive cell therapy, and low-dose IL-2 administration—several of which are now being actively evaluated in clinical trials as promising approaches for restoring immune tolerance in autoimmune diseases (72, 73).

4.1.1 Regulatory T cells in rheumatoid arthritis

Rheumatoid arthritis (RA) is a prevalent systemic chronic inflammatory disorder marked by symmetric polyarthritis, which may lead to bone and cartilage erosion and ultimately result in disability (74). Notably, a meta-analysis by Morita et al. (75) revealed that while peripheral blood Treg counts are reduced in RA patients, their abundance is increased in synovial fluid. Nevertheless, these results remain controversial, attributed to the intrinsic heterogeneity of RA and the absence of universally accepted Treg phenotypic markers. Additionally, the transient upregulation of FoxP3 and CD25 following T cell activation in the human immune system complicates the interpretation of data in autoimmune diseases with enhanced T cell activation, highlighting the need for cautious analysis of such findings.

Parallel to observations in RA, Tregs from patients with juvenile idiopathic arthritis (JIA) display features of immune dysregulation, including reduced FoxP3 stability, downregulated CD25 expression (76), altered cytokine and chemokine secretion (77), and diminished responsiveness to IL-2 (76). Notably, in vitro studies have shown that Tregs isolated from the peripheral blood or synovial fluid of JIA patients can recover their suppressive capacity once removed from the joint microenvironment (76). This finding suggests that the impaired Treg function observed in the joints of RA and JIA patients is likely not caused by an inherent defect in the Tregs themselves, but rather by the local inflammatory milieu (78). Proinflammatory cytokines—most prominently IL-6—play a pivotal role in inducing Treg instability and fueling inflammatory responses in arthritic conditions. In IL-6-mediated arthritis, CD4⁺ CD25^low FoxP3⁺ T cells are prone to losing FoxP3 expression (thus becoming ex-FoxP3 cells) and differentiating into pathogenic Th17 cells, which proliferate within inflamed joints (79). This mechanism underscores how the inflammatory microenvironment can compromise Treg function in arthritic diseases.

Over the past decade, mechanistic studies have emphasized that qualitative defects—rather than absolute Treg counts—better explain regulatory failure in RA (80, 81) Synovial Tregs often show altered expression of canonical markers (FOXP3, CTLA-4, CD25, Helios) and exhibit “fragilization,” a state marked by reduced suppressive capacity and enhanced susceptibility to pro-inflammatory reprogramming. Reduced expression of Ikaros family transcription factors (Helios, Aiolos, Eos) and incomplete demethylation of the FOXP3 TSDR correlate with diminished lineage stability and heightened disease activity, suggesting potential applications as biomarkers for disease stratification (27, 82, 83).

Taken together, existing findings demonstrate that RA is defined not by a mere numerical shortage of Tregs but rather by substantial impairments in Treg stability and functional capacity, orchestrated by chronic inflammation and local tissue-derived signals. Therapeutic strategies targeting Tregs hold considerable potential. In a murine collagen-induced arthritis model, adoptive transfer of Tregs markedly mitigated joint destruction through the suppression of T and B cell activity, as well as the inhibition of osteoclast-driven bone resorption (84). These findings underscore the potential of Tregs as a feasible therapeutic approach for autoimmune conditions marked by heightened proinflammatory cytokine production.

4.1.2 Regulatory T cells in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is defined as a chronic systemic autoimmune condition marked by diverse clinical features, the formation of autoantibodies, and a fundamental failure of immunological self-tolerance (85). A decrease in circulating Treg numbers is often observed during active SLE, and this numerical decline frequently correlates with the clinical severity of the disease (86). Evidence from murine lupus models suggests that therapeutic strategies focused on Tregs hold significant promise for improving the management of SLE (68). For instance, when lupus-prone (SWRxZNB)F1 mice received a subcutaneous administration of 1 μg of nucleosomal histone peptide autoepitopes, they successfully generated potent CD4⁺CD25⁺ and CD8⁺ Tregs. Crucially, these Tregs effectively reduced lupus-associated autoimmunity without inducing systemic immunosuppression, allergic responses, or anaphylaxis. Following adoptive transfer, these cells demonstrated the capacity to halt the migration and accumulation of pathogenic autoimmune cells in critical target sites, specifically the kidneys of lupus nephritis-susceptible mice, alongside suppressing autoantibody production and autoantigen recognition (87). Consistent with animal studies, multiple human investigations have documented a reduced prevalence of Tregs in SLE patients (86, 88). Moreover, Tregs isolated from individuals with active SLE exhibit a compromised ability to suppress the proliferation and cytokine secretion of CD4⁺ T effector cells in vitro. This functional deficit is linked to lower expression levels of both FoxP3 mRNA and protein (89).

4.1.3 Regulatory T cells in primary Sjogren’s syndrome

Primary Sjögren’s syndrome (pSS) is recognized as a systemic autoimmune disorder fundamentally defined by the infiltration of lymphocytes into the salivary and lacrimal glands (90). Though exocrine glands are the principal targets, pSS can affect various other organ systems. T cell-driven mechanisms are widely considered central to pSS pathogenesis, ultimately resulting in B cell overactivity. The activation of T cells promotes the loss of self-tolerance and facilitates the release of pro-inflammatory cytokines—including IFN-γ, IL-17, and IL-21—which drive local inflammation (90). The exact contribution of Tregs to pSS pathophysiology remains unsettled, given that published studies report conflicting results, describing Treg frequencies as normal, elevated, or diminished (68). Furthermore, the localization and presence of Tregs within the salivary glands, the primary target organ, are also points of debate. Certain investigations have established a positive correlation between the degree of CD4⁺FoxP3⁺ T cell infiltration in lymphocytic sialadenitis and biopsy severity scores. Conversely, other reports have indicated a marked scarcity or absence of Tregs within the inflamed glands, even when the count of circulating Tregs remains stable (68).

4.1.4 Regulatory T cells in experimental autoimmune encephalomyelitis, multiple sclerosis, and Parkinson’s disease

Tregs are instrumental in managing the autoimmune response in experimental autoimmune encephalomyelitis (EAE), the most common animal model for multiple sclerosis (MS). MS is characterized by demyelination and inflammation within the central nervous system (CNS), alongside a marked infiltration of lymphocytes (91). Studies in mice demonstrate that intentional T cell depletion can provoke spontaneous autoimmune disease, while conversely, boosting Treg activity can mitigate or prevent various EAE manifestations (92). Adoptive transfer of Tregs has been shown to substantially reduce the clinical severity of EAE, suggesting that CD4⁺CD25⁺ Tregs suppress both CNS inflammation and antigen-specific autoreactive immunity during the active phase of the disease (93). In vitro, data confirm that Tregs are potent inhibitors of CD4⁺ T cell-dependent Th1 cytokine production, particularly in response to myelin oligodendrocyte glycoprotein (MOG) (94). Notably, in MOG-induced EAE models, induced Tregs (iTregs) demonstrate comparable efficacy to natural FoxP3⁺ Tregs in halting disease progression (95).

One promising experimental therapeutic strategy for EAE involves a Salmonella vaccine engineered to express the anti-inflammatory colonization factor antigen 1 (Salmonella CFA/1) (96). This vaccine was shown to elevate the population of CD4⁺CD25⁺FoxP3⁺ Tregs and successfully inhibited EAE onset in SJL mice. The Tregs generated by this specific vaccine were even more effective in EAE prevention compared to naive Tregs or those induced by the standard Salmonella vector alone. Other experimental treatments also offer hope for EAE. For instance, both the transfer of CD4⁺CD25⁺ T cells and myelin basic protein (MBP)-specific receptor-modified T cells have been utilized to prevent and treat MBP-induced EAE. Furthermore, the heparin-binding growth factor midkine (MK), whose levels are markedly increased in the spinal cord during EAE development, plays roles in inflammation, tissue repair, and oncogenesis (97, 98). Deficiency of MK was found to alleviate MOG-induced EAE by increasing Treg frequency in peripheral lymph nodes and simultaneously suppressing autoreactive Th1 and Th17 cells. Given that MK is a potent inhibitor of Treg proliferation, blocking it with RNA aptamers represents a potential new treatment avenue for autoimmune diseases, as its neutralization effectively expands Treg populations and lessens EAE symptoms (99).

Parkinson’s disease (PD), the second most prevalent neurodegenerative condition after Alzheimer’s disease, involves the progressive loss of dopaminergic neurons in the substantia nigra and their projections into the caudate-putamen (100). The neuroprotective effects demonstrated by Tregs in animal models of PD underscore the potential for Treg-based therapies to slow neurodegeneration and preserve dopaminergic neurons (101).

4.1.5 Regulatory T cells in inflammatory bowel disease

Inflammatory bowel disease (IBD), a category encompassing Crohn’s disease and ulcerative colitis, impacts an estimated 0.3% of individuals in Western countries (102). Tregs have been shown to be essential for both preventing and resolving colitis, particularly in animal models of gut inflammation (103). The therapeutic effect of CD4⁺CD25⁺ Tregs in colitis involves the restoration of normal intestinal structure and a decrease in leukocyte infiltration within the intestinal lamina propria (104). A substantial number of Tregs have been found in both the inflammatory lesions and the mesenteric lymph nodes (105). Their ability to curb the accumulation of effector cells in the colon suggests they may be capable of arresting the progression of colitis (106). In patients with active Crohn’s disease, while FoxP3⁺CD4⁺ Treg cells are often diminished in the peripheral circulation, their concentration is typically increased within mucosal lymphoid tissues, including the lamina propria and mesenteric lymph nodes (107). These cells frequently congregate in sites of active inflammation, such as granulomas. An exciting finding in a chronic T cell-dependent colitis model involved the parenteral delivery of filamentous hemagglutinin (FHA) from Bordetella pertussis to severely immunocompromised mice. This approach successfully lowered the counts of Th1 cells and pro-inflammatory cytokines, activated Tregs, and reduced disease activity (108). This result is particularly compelling because FHA appears to be a viable candidate for clinical evaluation in patients with Crohn’s disease.

4.1.6 Regulatory T cells in autoimmune diabetes

Type 1 diabetes (T1D), also known as insulin-dependent diabetes mellitus, is an autoimmune disorder resulting from the immune system’s destructive targeting of pancreatic β cells. The inbred non-obese diabetic (NOD) mouse model, which spontaneously develops an autoimmune diabetes highly analogous to human T1D, is a critical tool for mechanistic studies (109). In NOD mice, the dynamic balance between diabetogenic T cells and Tregs is crucial for regulating diabetes progression, with disease onset often linked to a progressive loss of Treg function (110, 111). Adoptingly transferring islet-specific Tregs can prevent both established and early insulitis, conferring protection against spontaneous diabetes (112). Additionally, polyclonal Tregs or adaptive Tregs derived from normal CD4⁺ populations are capable of reversing the disease shortly after diagnosis. These cells mature into FoxP3⁺CD25^- memory Tregs, which offer durable protection against relapse (112). A noteworthy recent investigation showed that a small count of pancreatic islet-antigen-specific Tregs was substantially more efficacious at preventing and treating diabetes in NOD mice than a far greater number of polyclonal Tregs (113). Moreover, autoimmune diabetes can be prevented in Treg-deficient NOD mice by culturing and utilizing Tregs that are specific to islet peptide mimics (114, 115). These observations provide support for the concept that naturally existing autoantigen-specific Tregs could be harnessed for the therapy of organ-specific autoimmunity. As the disease advances, Tregs selectively traffic to the pancreas, where they inhibit T effector cell activity to manage the later phases of diabetogenesis. Nevertheless, Treg-mediated control is compromised with age, as Tregs show reduced proliferation within the pancreas and decreased functional capacity, raising susceptibility to the disease (116). Furthermore, an association has been established between Coxsackievirus B₄ (CB₄) infections and T1D induction (117). Interestingly, Tregs produced during CB4 infection under the influence of TGF-β demonstrated an ability to protect against T1D development without impairing the necessary antiviral immunity. This suggests a potential avenue for infection-mediated immune regulation in preventing insulin resistance.

4.1.7 Regulatory T cells in chronic kidney disease

Glomerulonephritis is a major contributor to chronic kidney disease (CKD) and end-stage renal disease, and although some kidney injuries are non-immune, it is primarily viewed as an immune-mediated condition (118). Tregs possess a substantial ability to modulate both the extent of tissue injury and subsequent repair mechanisms in various renal disorders (119). Investigations into the therapeutic potential of these cells in animal models indicate that treatment approaches focused on Tregs could be advantageous for both preventing and managing kidney disease in humans (120, 121).

Tregs have been demonstrated to be powerful suppressors of anti-glomerular basement membrane (anti-GBM) glomerulonephritis, a severe autoimmune disease affecting the kidney (122). Tracing experiments using GFP-labeled Tregs revealed that, contrary to expectation, these cells mainly accumulated in the spleen and lymph nodes draining the kidney, rather than directly infiltrating the kidneys of mice with nephritis (120). Interestingly, Treg administration did not reduce the formation of immune complexes in the glomeruli. Instead, they lessened end-organ damage by inhibiting the activation of immune cells within the adjacent lymph nodes. In the context of Goodpasture’s syndrome, a human autoimmune disorder, T cells specific for collagen exhibited an inflammatory profile during active phases but transitioned to a regulatory function during remission, which highlights the central role Tregs play in resolving this autoimmune response (123). Furthermore, in the adriamycin nephropathy mouse model of chronic proteinuric renal disease, naive T cells were genetically modified by retroviral transduction with the FoxP3 gene to produce FoxP3-transduced Tregs. These modified cells displayed a regulatory profile, successfully suppressed the in vitro proliferation of CD4⁺CD25⁺ T cells, and in vivo reduced both glomerular and interstitial damage, thereby preserving renal structure and function (121). Nevertheless, obstacles related to vector delivery have made gene therapy aimed at the kidney challenging (124). Although the strategy of utilizing Tregs to impede or stop the advancement of renal disease is attractive, comprehensive, disease-specific research and meticulously planned clinical trials are mandatory before these treatments can be routinely applied to human patients.

4.1.8 Regulatory T cells in autoimmune gastritis and acquired aplastic anemia

Autoimmune gastritis (AIG) is a spontaneously occurring and rare animal model for organ-specific autoimmunity. Its primary target antigen is the gastric parietal cell proton pump, H-K-ATPase (125). AIG also functions as a mouse model for human pernicious anemia, characterized by T and B cell reactivity against H-K-ATPase. A study by Khalilollah et al. established that T effector (Teff) cells, specifically Th1, Th2, and Th17 subsets, drive AIG pathology, with each subset generating unique histological patterns of tissue injury. Notably, Th17 cells were identified as the subset causing the most widespread gastric destruction via cellular infiltration (126). In contrast, the concurrent transfer of naturally occurring polyclonal Tregs was effective at completely preventing AIG development. Although Tregs were very successful in mitigating Th1 and Th2 cell-mediated pathology, their efficacy in controlling Th17-induced AIG was limited to the disease’s initial stages (127). Turning to acquired aplastic anemia, contemporary evidence suggests that patients with the condition have significantly reduced circulating levels of Tregs (128). In murine models, Treg infusion has been shown to decelerate disease progression. Further human research indicated that virtually all aplastic anemia patients had a lower frequency of Tregs at the time of diagnosis, coupled with significantly diminished expression of FoxP3 and the critical immune-regulatory transcription factor, NFAT1 protein (129).

4.1.9 Regulatory T cells in Hashimoto’s thyroiditis

Hashimoto’s thyroiditis (HT) is an organ-specific autoimmune condition defined by the infiltration of lymphocytes into the thyroid gland, which culminates in the destruction of follicles (130). Experimental Autoimmune Thyroiditis (EAT) is a validated mouse model used to investigate HT (113). Studies have demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) fosters the generation of both IL-10-producing Tregs and semi-mature dendritic cells (DCs). This evidence proposes GM-CSF as a potential therapeutic agent for EAT and for other autoimmune diseases sharing similar underlying pathology. A crucial finding is that IL-10 directly suppresses mouse thyroglobulin-specific T effector cells, underlining its vital function in controlling the disease in mice treated with GM-CSF (131). Furthermore, semi-mature DCs loaded with thyroglobulin exhibit tolerogenic characteristics that effectively stop EAT progression by facilitating the proliferation of thyroglobulin-specific Tregs. Apart from their function in thyroid autoimmunity, Tregs have also been suggested to play a role in the transition of hyperthyroid Graves’ disease into HT and hypothyroidism (132).

4.1.10 Regulatory T cells in psoriasis

Psoriasis is a systemic inflammatory disorder influenced by a combination of environmental factors and genetic susceptibility (133). In an immunocompetent state, Tregs rigorously control the secretion of Type 1 and Th17 cytokines, both of which are central pathogenic drivers of psoriasis. By inhibiting these pro-inflammatory cell types, Tregs maintain immunological equilibrium and help guard against autoimmune conditions, including psoriasis and other dermatological issues (134). A failure in Treg-mediated suppressive function is hypothesized to shift the Th17/Treg balance in psoriasis, a shift that has been associated with worsened disease presentation. Nevertheless, the exact molecular basis for Treg dysfunction in psoriasis has yet to be fully elucidated. Despite the widely accepted importance of Tregs for therapeutic approaches in psoriasis, the connection between the cellular concentration of Tregs and the clinical severity of the disease is still a matter of ambiguity (135, 136).

4.2 Regulatory T cells in allergic diseases

This section comprehensively examines the distinct roles and functional impairments of Tregs across major allergic conditions, including allergic rhinitis (AR), allergic asthma, food allergy (FA), and atopic dermatitis (AD). It focuses on how alterations in the frequency, phenotypic characteristics, and suppressive function of Tregs contribute to the underlying disease pathology, and further evaluates the therapeutic viability of Treg-based interventions.

4.2.1 Regulatory T cells in allergic rhinitis

Allergic rhinitis (AR) is a pervasive, chronic inflammatory disorder affecting the upper respiratory tract, impacting an estimated 20% to 30% of adults and up to 40% of children across the United States and Europe (137, 138). Its complex pathophysiology involves inflammation of the nasal mucosa, orchestrated by a sophisticated network of immune cells, notably ILC2s, dendritic cells (DCs), Th2 cells, follicular T helper (Tfh) cells, follicular regulatory T (Tfr) cells, and B cells (139, 140).

Tregs are widely recognized for their potent capability to regulate and inhibit allergen-specific immune responses (141). Across numerous studies in AR patients, a consistent finding is the diminished count of circulating FoxP3⁺ Tregs, alongside a reduced in vitro ability to suppress Th2-driven responses when compared to healthy controls (142). Concomitantly, decreased FoxP3 expression levels have been observed within the nasal mucosa of AR subjects (143–145), which may correlate with the clinical severity of the condition (146). Genetic research has established links between specific FoxP3 gene polymorphisms and AR, implying that these variations might compromise Treg functionality and heighten susceptibility to allergic reactions (147). Furthermore, an elevated proportion of immunoglobulin-like transcript 3-positive (ILT3+) Tregs, characterized by lower FoxP3 expression and impaired suppressive capacity, has been identified in AR cohorts (148, 149). Patients with AR also exhibit lower levels of suppressive IL-35-producing Tregs (iTr35) and circulating IL-10-producing Tr1 cells (150). Additional reports highlight decreased frequencies of CD8⁺CD25⁺CD137⁺ Tregs and Tfr cells in the nasal mucosa, peripheral blood, and tonsils of individuals with AR (151, 152). Conversely, some data suggest a higher relative abundance of IL-17A-secreting, FoxP3- T cells (potentially indicative of plastic Tregs or Th17-like cells) in the AR population compared to non-allergic controls.

One investigation utilizing a murine AR model detected a lower population of Helios+ Tregs in the nasal mucosa and splenic cells of AR mice relative to controls. This observation proposes that defective Treg suppressive activity facilitates the excessive activation of T helper cells, such as Th2 cells, and subsequently promotes disease onset. The study also determined that approximately 75% of CD25⁺FoxP3⁺ Tregs co-expressed Helios⁺, suggesting that while the FoxP3⁺Helios⁺ subset is a major component, the combined FoxP3⁺CD25⁺ marker captures a larger overall Treg population in both AR and control groups (153). In a separate study, it was demonstrated that Notch2 can directly enhance the transcription of FoxP3, speculating that this mechanism fosters Treg differentiation and function. This, in turn, could inhibit pro-inflammatory and effector T cell responses, leading to a significant mitigation of the allergic inflammatory response characteristic of AR (154). Collectively, the evidence points toward a reduction in both the absolute number and the functional potency of Tregs in AR, which profoundly influences its pathophysiology and clinical course. Consequently, the restoration of normal Treg function is regarded as a pivotal therapeutic objective in the management of AR.

4.2.2 Regulatory T cells in allergic asthma

Allergic asthma is a persistent respiratory condition initiated by allergic hypersensitivity to specific environmental allergens, presenting with hallmark features like airway hyperresponsiveness, elevated immunoglobulin E (IgE) levels, and chronic inflammation of the airways (155). Common sensitizing agents include dust mites, animal dander, pollen, and fungi. The inflammatory process in allergic asthma is primarily a Th2-mediated reaction, engaging both the innate and adaptive immune systems (156). CD4⁺ Th2 cells secrete characteristic cytokines (IL-4, IL-5, IL-9, and IL-13), which collectively drive eosinophil recruitment to the airway wall, induce mucus hypersecretion, and stimulate IgE synthesis by allergen-specific B cells, culminating in the massive degranulation of mast cells and release of inflammatory mediators (157).

Treg dysfunction is a critical factor in asthma pathogenesis, as it disrupts the essential process of immune tolerance. Within the lung environment, Tregs play a role in promoting the differentiation of regulatory B cells and biasing DCs toward a tolerogenic phenotype, which collectively impedes initial sensitization and IgE synthesis upon allergen encounter (141). Pulmonary Treg populations inhibit key effector cells in allergic asthma, including Th2 cells, mast cells, eosinophils, basophils, and ILC2s. This suppression is achieved through soluble mediators such as IL-10, TGF-β, and IL-35, as well as via cell-surface inhibitory molecules like PD-1 and CTLA-4 (158). Early experimental work in mouse models established that the selective depletion of CD4⁺CD25⁺ Tregs exacerbated airway hyperresponsiveness, increased IL-4 and IL-5 production, and heightened the influx of T cells and neutrophils into the airways during allergic asthma (159).

Given the Th2-driven nature of allergic asthma, Tregs, owing to their capacity to inhibit Th2 activation, are fundamentally important. Studies examining Treg counts in asthma, however, have yielded contradictory outcomes. One research group reported a decline in lung Tregs among asthmatic children, which they correlated with suppressed pulmonary Th2 reactivity (160). Conversely, other investigations suggested a trend toward an increased number of Tregs residing in the airways of patients afflicted with moderate to severe asthma, relative to healthy individuals (161). These disparities likely stem from differences in study populations and the methodologies employed for Treg enumeration. Adding further complexity, some evidence suggests that low Treg counts and functional impairments may predispose younger patients (children and young adults) to asthma, whereas the correlation between Tregs and asthma risk or severity appears less pronounced in older patients (162).

Alveolar macrophages and pDCs have been pinpointed as vital cell types that promote FoxP3+ Treg differentiation within the lung microenvironment (153). In individuals with severe asthma, a reduction in the number of FoxP3⁺ Tregs has been documented in both peripheral blood and bronchoalveolar lavage fluid (BALF) samples when compared to healthy subjects (163–167). This numerical decrease is frequently accompanied by a compromised ability of Tregs to chemotax toward lung epithelial cells (165, 168). Additionally, FoxP3⁺ Tregs from these patients exhibit reduced expression of CCR5, suggesting impaired suppressive activity that correlates with worsened lung function (166). Furthermore, Tregs in asthma exhibit elevated expression of CRTH2, a Type 2 receptor for prostaglandin D2, which is associated with asthma control and exacerbations (165). Thus, allergic asthma is characterized by both reduced Treg numbers and altered surface marker expression (e.g., low CCR5 and high CRTH2), collectively pointing to impaired function and a susceptibility to Th2-skewed inflammatory responses (166).

A considerable body of research underscores the profound influence of environmental factors on asthma exacerbation. For instance, exposure to elevated levels of ambient air pollution is a recognized risk factor, potentially mediated by epigenetic modifications affecting Treg function. A study by Prunicki et al. (167) demonstrated distinct patterns of FoxP3 gene methylation in asthmatic subjects exposed to air pollution compared to non-asthmatic controls under similar exposure conditions. More recent studies further link changes in DNA methylation within the FoxP3 promoter region to subsequent impairment of regulatory T cell function (169). Common atmospheric contaminants, including carbon monoxide (CO), nitrogen dioxide (NO₂), polycyclic aromatic hydrocarbons (PAHs), and particulate matter (PM), induce altered CpG methylation at the FoxP3 locus. This mechanism compromises Treg activity and worsens asthma phenotypes (170). Additional research indicates a strong correlation between exposure to air pollutants in children and FoxP3 methylation levels, associating with Treg dysfunction and increased plasma IgE (170). Moreover, exposure to inhalable particulate matter has been shown to disturb the critical Treg/Th17 balance, aggravating asthma via a mechanism dependent on the aryl hydrocarbon receptor (AHR). Following PM-induced Ahr activation, the Notch ligand JAG1 is expressed, which destabilizes iTregs and promotes allergic airway inflammation. Recent findings identify Notch4 as a relevant Notch receptor on Tregs that is upregulated in circulating Tregs from asthmatic patients in an IL-6-dependent manner, correlating with disease severity (171, 172). Notably, blocking the IL-6 receptor signaling pathway enhances Treg suppressive function and downregulates Notch4 expression, offering a potential therapeutic benefit for patients with severe asthma (173, 174).

In summary, compelling evidence suggests that Tregs are central to the pathogenesis of allergic asthma. The disease pathology is frequently exacerbated by reduced numbers and impaired function of Tregs in the lungs, positioning Tregs as a valuable target for potential therapeutic interventions.

4.2.3 Regulatory T cells in food allergy

Food allergy (FA) constitutes a major global public health concern, with its prevalence escalating rapidly in recent decades. It is defined by predictable IgE-mediated adverse reactions upon consumption of specific foods (175, 176). Surveillance data from the United States indicate that approximately 7.6% of children are affected by FA, with a notable 18% surge in prevalence reported between 1997 and 2007 (175, 176). In the UK, the rate of hospital admissions for FA in young children increased by 6.6% annually between 1998 and 2018 (177).

FA is thought to emerge from a complex interplay of genetic predisposition, a history of atopy, family history of allergies, shifts in hygiene practices, and the timing and route of food antigen exposure (178). In pediatric populations, the most frequent allergens include peanuts, milk, nuts, and eggs, while adults are more commonly affected by fish, shellfish, nuts, and peanuts (179–181). Oral tolerance, the body’s natural state of immunological unresponsiveness to antigens ingested orally, is a fundamental protective mechanism. Its failure triggers a pathogenic Type 2 immune response, marked by the synthesis of high-affinity IgE antibodies against food antigens (182). Allergen sensitization can occur not only through the gastrointestinal tract but also via the respiratory tract or the skin. Once the epithelial barrier is compromised, antigen-presenting cells (APCs)—such as macrophages and dendritic cells (DCs)—process and present allergens to T cell receptors, initiating a Th2-type immune response and the subsequent generation of antigen-specific IgE (183). This IgE then cross-links with FcεRI receptors on basophils and mast cells, leading to their degranulation and the swift release of inflammatory mediators (175, 184). The resulting rapid symptoms can include urticaria, rash, or gastrointestinal upset. In severe instances, life-threatening complications like anaphylaxis or cardiovascular/respiratory abnormalities may arise (See Figure 4 for an overview of allergic disease mechanisms) (185, 186).

Figure 4

Figure 4. Tregs in food allergy (FA). Treg cells restrain IL-33–induced expansion of ILC2s in the intestinal mucosa, thereby reducing IL-4 production. RORγt⁺ antigen-presenting cells (APCs), including type 3 innate lymphoid cells (ILC3s) and Thetis cells (TCs), sample commensal antigens from the intestinal lumen and promote activation of RORγt⁺ induced Treg (iTreg) cells. These commensal-induced RORγt⁺ Tregs, via a TGF-β1–dependent mechanism, maintain intestinal immune tolerance in food allergy by suppressing mast cell activation and allergen-specific Th2 responses.

Tregs are unequivocally established as pivotal in the induction of oral tolerance. The process by which DCs stimulated by food antigens generate Tregs is intricate, encompassing multiple dependent mechanisms, including those reliant on retinoic acid, indoleamine 2,3-dioxygenase (IDO), or TGF-β. The expression of integrin α4β7 and CCR9 on induced Tregs governs their directed homing to the gut (187). Moreover, metabolites derived from the gut microbiota significantly contribute to the initiation of tolerogenic pathways (188–190). As noted, the indispensable role of Tregs in preventing Type 2 cytokine secretion and mast cell degranulation underscores their function in curtailing the progression of allergic reactions (191). Indeed, FA has been linked to compromised functionality and generation of allergen-specific Tregs, as demonstrated in a mouse model with enhanced IL-4 receptor signaling (Il4ra^F709) (192). Furthermore, the adoptive transfer of Tregs has been shown to prevent anaphylaxis in a murine model of ovalbumin-induced FA (193). Patients diagnosed with FA have consistently been reported to have a lower percentage of circulating Tregs compared to healthy counterparts (194–196). Additionally, the normal age-related increase in CCR6 expression observed on FoxP3⁺ Tregs from healthy individuals was absent in children with food allergies. This deficiency in CCR6 expression may impede Treg migration to peripheral inflammatory sites, thereby hindering tolerance induction (194). In recent years, substantial research has highlighted the influence of epigenetics on oral immune tolerance. Oral immunotherapy (OIT) using peanut protein has been shown to increase the population of antigen-specific Tregs and enhance DNA demethylation at the FoxP3 gene locus (195). These specific epigenetic alterations have been attributed to IDO-expressing DCs isolated from participants undergoing OIT (195). In a murine peanut allergy prevention model, the administration of high (but not low) doses of peanut before sensitization successfully induced tolerance and elevated the percentage of CD4⁺CD25⁺FoxP3⁺ cells in mesenteric lymph nodes (MLN) (196). The study found that tolerized mice exhibited lower methylation levels of the critical regulator FoxP3 compared to mice sensitized to peanut protein (196). Finally, dietary components have been proposed to function as epigenetic regulators, potentially offering a means to restore the dysregulated immune balance associated with food allergies.

The host’s intestinal immune system is continuously challenged by, and interacts with, immunogenic molecules and antigens derived from both ingested food and the intestinal commensal microbiota. In the neonatal period, the gut environment is predominantly colonized by species such as Lactobacilli and Bifidobacteria. These early residents secrete specific neurotransmitters that stimulate Treg activation early in life, a process crucial for establishing long-term immunological tolerance to dietary antigens (197). The shift toward solid food during weaning promotes the proliferation of the Clostridium and Bacteroidetes phyla. This microbial transition subsequently drives the robust induction of a specialized Treg subpopulation termed RORγt⁺ Tregs (197). Induced by gut microbiota early in life, RORγt⁺ Tregs persist into adulthood and contribute to tolerance toward food and commensal antigens by suppressing pathogenic Th1, Th2, and Th17-mediated immune responses (198). Notably, MHCII⁺RORγt⁺ antigen-presenting cells (APCs)—distinct from conventional dendritic cells (DCs)—have been identified as key regulators of RORγt+ Treg differentiation (199, 200). These RORγt⁺ APCs comprise type 3 innate lymphoid cells (ILC3s) and a recently characterized cell type called Thetis cells. Both ILC3s and Thetis cells mediate RORγt⁺ Treg induction through TGF-β1 signaling, which relies on an αVβ integrin-dependent mechanism, with Thetis cells exerting a dominant role in early life (see Figure 4). Additionally, the development of RORγt⁺ Tregs is guided by immunogenic signals from the microbiota, such as polysaccharides and secondary bile acids (201, 202).

In conclusion, regulatory Tregs are undeniably critical for maintaining immune tolerance to food antigens. Deficiencies in Treg induction or functional competence profoundly impact the onset of allergic responses. As such, targeting Tregs to restore immune tolerance represents a prominent therapeutic strategy for the management of food allergies.

4.2.4 Regulatory T cells in atopic dermatitis

Atopic dermatitis (AD), commonly referred to as eczema, is a widespread inflammatory cutaneous disorder that impacts roughly 2–3% of adults and 10–20% of children (203). Distinguishing features include impaired skin barrier function, aberrant cellular immune responses, and heightened susceptibility to environmental allergens—with Th2 cell overactivation serving as a central driver (204). Key pathological traits of AD lesions encompass the infiltration of activated Th2 cells and eosinophils, alongside the expansion of ILC2s, secretion of IL-4 and IL-13, and increased concentrations of total and allergen-specific IgE (205). These pathological hallmarks correlate directly with disease severity. Notably, Tregs are highly enriched in the skin of both humans and mice, where they play a critical role in regulating allergic inflammation and facilitating tissue repair (206–208).

Skin-resident Tregs are established in early life and contribute to the induction of tolerance toward the cutaneous microbiota (209, 210). A large proportion of skin Tregs express the transcription factor GATA3 (211, 212), which aligns with their role in tissue repair alongside other type 2 immune components, such as ILC2s and Th2 cells. Emerging data indicate that these Tregs also express the retinoic acid receptor-related orphan receptor α (RORα)—a molecule thought to constrain dysregulated type 2 immune reactions within the skin (213). Furthermore, skin Tregs express alarmin receptors, including IL-33R and TSLPR (214, 215). This capacity to sense tissue damage enables Tregs to co-mobilize with the subsequent type 2 immune response, promoting tissue repair through alarmin-induced production of amphiregulin (Areg).

Tregs’ ability to modulate immune responses and infiltrate cutaneous tissues strongly implicates them in AD pathogenesis (216). Genetic conditions that disrupt Treg function—including Immunodeficiency, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome and Wiskott-Aldrich syndrome (WAS)—offer strong support for this involvement (217). These disorders involve Treg dysfunction due to FoxP3 mutations or defective Wiskott-Aldrich syndrome protein, respectively, and their associated eczematous skin lesions closely resemble AD, underscoring the role of impaired Tregs in AD development (218). Similarly, Treg-deficient scurfy mice develop eczematous dermatitis that mimics AD lesions. Additionally, several treatments for allergic disorders that generate or modulate Treg function—such as allergen immunotherapy (AIT) and vitamin D supplementation—have demonstrated clinical benefits in AD patients, potentially by increasing Treg numbers or enhancing their suppressive capacity (219, 220).

In the context of AD-related immune dysregulation, the role of the altered cutaneous microbiome in driving Treg dysfunction is particularly noteworthy. Skin Tregs colocalize with commensal bacteria at hair follicles (221, 222), and their reduced abundance in germ-free mice highlights the microbiome’s role in promoting skin Treg expansion (223). The cutaneous microbiome of AD patients is typically dominated by Staphylococcus aureus (S. aureus) strains, many of which secrete superantigenic toxins (223). Patients with severe AD often exhibit a predominance of S. aureus, whereas Staphylococcus epidermidis is more prevalent in milder disease (224). Notably, S. aureus isolates from AD patients experiencing severe flares induce epidermal thickening and expansion of cutaneous Th2 and Th17 cells in a murine skin colonization model (225). A related study found that impaired skin Treg-mediated immunoregulation promotes type 2 cytokine production by commensal-specific plastic Th17 cells (226). These findings point to a convergence of cutaneous processes in AD: skin Treg dysfunction, dysregulated Th2 immunity, and microbiome alterations—all of which merit further investigation.

In summary, Tregs’ contribution to AD pathogenesis is multifaceted and continues to be an area of active investigation. Defects in Treg function and their interactions with the cutaneous microbiome are clearly implicated in disease development. A comprehensive phenotypic and mechanistic analysis of Tregs during AD cutaneous flares is essential to better understand their role in the disease and to guide the development of effective Treg-based therapeutics for AD.

4.3 Regulatory T cells as central mediators of tolerance in autoimmune and allergic diseases

Conventionally, autoimmune diseases—often characterized by Th1/Th17-predominant responses—and allergic disorders—primarily driven by Th2 signaling cascades—have been viewed as distinct immunopathological conditions. Yet, through the prism of regulatory T cells (Tregs), both disease categories unite around a common fundamental impairment: the breakdown of core immune tolerance mechanisms. This shared feature is illustrated in Table 2, which outlines aberrant Treg alterations across both autoimmune and allergic spectra. A defining trait of both disease types lies in Treg abnormalities, either numerical reductions or functional deficits. For instance, in autoimmune conditions like RA and SLE, Treg populations may show diminished counts or compromised suppressive capacity (86). Similarly, in allergic disorders such as AD and asthma, Treg numbers might remain unaltered or even elevated, but their suppressive efficacy is frequently impaired—especially in the context of allergen-specific immune responses (142, 146). Beyond this overlap in Treg function, both disease groups exhibit disruptions in the cytokine microenvironment and Treg/Th17 balance. In autoimmune settings like psoriasis, as well as allergic manifestations such as severe AD, inadequate Treg-mediated suppression coincides with heightened Th17 cell activity (135, 136). While transforming growth factor-β (TGF-β) acts as a key driver of Treg differentiation, its crosstalk with proinflammatory mediators like interleukin-6 (IL-6) can redirect cellular differentiation toward Th17 lineages. These Th17 cells then secrete cytokines such as IL-17, perpetuating inflammatory tissue damage. As a result, the inflammatory microenvironment in both autoimmune and allergic diseases contributes to pathogenesis by disrupting the Treg/Th17 equilibrium. Furthermore, Treg function and differentiation are profoundly shaped by epigenetic regulation and microbial cues. Gut commensal bacteria—including Clostridium species—facilitate Treg maturation and functional competence, with their metabolites (e.g., short-chain fatty acids, SCFAs) enhancing Treg performance through mechanisms such as histone deacetylase (HDAC) inhibition (188–190). Thus, microbiota dysbiosis emerges as a key contributing element to the development of both disease categories.

Table 2

Table 2. Abnormal changes of Treg cells in autoimmune and allergic diseases.

Given these convergent immunoregulatory pathways, Treg-targeted therapeutic modalities hold wide relevance across autoimmune and allergic disorders. These interventions aim to reinstate Treg-orchestrated tolerance and rectify underlying immune imbalances, moving beyond mere symptomatic control of inflammation to address root pathogenic mechanisms—representing a vital direction for future treatments. Key therapeutic strategies include: firstly, low-dose IL-2 administration to enhance in vivo Treg expansion and functionality; secondly, adoptive Treg transfer following ex vivo expansion of autologous or allogeneic cells; thirdly, antigen-specific immunotherapy to induce dedicated Treg populations via peptide-based or allergen desensitization approaches (219, 220); fourthly, epigenetic modulation using HDAC inhibitors or histone acetyltransferase (HAT) regulators to strengthen Treg competence (62); and lastly, microbiome-directed interventions such as probiotics or prebiotics to modulate Treg differentiation (197).

5 Therapeutic approaches of Tregs-based immunotherapy

5.1 Immunosuppressive agents

5.1.1 Corticosteroids

Corticosteroids represent extensively utilized immunosuppressive compounds, notably in managing severe allergic responses, autoimmune disease exacerbations, and post-organ transplantation care (227) (see Figure 5). Corticosteroids -mediated therapeutic benefits typically endure for several days to weeks post-administration, stemming from their extensive influence on the development and differentiation of diverse immune cell populations—including T cells, DCs, and macrophages (228–230).

Figure 5

Figure 5. Therapeutic approaches of Tregs-based immunotherapy. This figure summarizes current and emerging strategies that target or harness regulatory T cells (Tregs) to restore immune tolerance in autoimmune and allergic diseases. These approaches fall into three main categories: Conventional Immunosuppressants- Glucocorticoids, Rapamycin and statins; Biologicals- Interleukin-2 (IL-2), TNF receptor 2 (TNFR2) agonists, Intravenous immunoglobulin (IVIg) and Tregitopes; Treg-based Therapies- Polyclonal Tregs therapy, Engineered antigen-specific TCR-Treg therapy, Chimeric Treg therapy and Chimeric antigen receptor (CAR)-Tregs therapy. These complementary approaches modulate Tregs to reprogram immune homeostasis and advance precision immunotherapy for autoimmune and allergic diseases.

Corticosteroids exert a profound impact on T cell viability, maturation, and lineage commitment. They trigger apoptosis in conventional T cells (Tconv), consequently elevating the Treg/Tconv ratio. Beyond this, Corticosteroids enhance Treg abundance and functional potency through both direct and indirect cellular pathways (231). Directly, they stimulate TGF-β receptors, which precipitates the phosphorylation and nuclear translocation of SMAD2 and SMAD3 proteins. These signaling molecules then bind to the FoxP3 promoter, boosting FoxP3 expression and driving Treg differentiation from naive T cells (232). Indirectly, Corticosteroids modulate non-T cell populations like plasmacytoid DCs, which foster Treg development via both TLR-dependent and TLR-independent mechanisms (232). Additionally, they promote Treg expansion by inducing non-T cells to secrete increased levels of TGF-β (231).

In autoimmune diseases, Corticosteroids have been demonstrated to augment Treg proportions in a dose-responsive fashion—an effect observed in patients with SLE (233). High-dose dexamethasone therapy in individuals with immune thrombocytopenic purpura (ITP) also elevated Treg counts, with CD25⁺CD127^- Tregs reaching peak levels 14 days after Corticosteroids administration (234). In allergic disorders, studies focusing on asthma have shown that Corticosteroids can enhance Treg numbers and functionality. For example, topical Corticosteroids administration upregulated FoxP3 mRNA expression in peripheral blood mononuclear cells (PBMCs) of patients with moderate asthma (235). This was associated with elevated concentrations of IL-10 and TGF-β, suggesting these cytokines either originate from Tregs or promote the differentiation of pTregs. Another study reported that children with asthma receiving inhaled corticosteroids exhibited higher percentages of CD4⁺CD25^high T cells in their PBMCs and bronchoalveolar lavage fluid (BALF), with Corticosteroids restoring the suppressive activity of these Tregs (165). Similarly, a murine model of ovalbumin-induced asthma exhibited expanded Treg populations following prolonged Corticosteroids exposure, supporting the notion that mid- to long-term Corticosteroids effects include Treg expansion alongside immediate anti-inflammatory actions (236). Collectively, Corticosteroids administration in asthmatic patients yields both sustained increases in Treg counts and anti-inflammatory benefits.

Notably, Corticosteroids exert disease- and tissue-specific impacts on Treg numbers. While Corticosteroids-treated patients with SLE, ITP, asthma, and nickel allergy display increased Treg counts, the converse has been documented in psoriasis patients (237). Additionally, the outcomes of high-dose Corticosteroids in relapsed MS patients remain inconclusive (237). In summary, the influence of Corticosteroids treatment on Treg counts varies by disease type and tissue involvement. Given that Treg expansion may be pivotal for disease control, Corticosteroids treatment planning necessitates consideration of their effects on Treg counts—an aspect critical for optimizing therapeutic outcomes in immune-mediated disorders.

5.1.2 Rapamycin

Rapamycin (sirolimus), a macrolide antimicrobial compound derived from Streptomyces hygroscopicus, serves as a potent agent for mitigating allograft rejection (238) (see Figure 5). Like cyclosporine A and FK506 (tacrolimus), it interacts with the intracellular immunophilin FK506-binding protein (FKBP12) (239). Unlike these immunosuppressants—which obstruct T-cell receptor (TCR)-triggered activation—rapamycin dampens cytokine-mediated signaling through its action on the mammalian target of rapamycin (mTOR), a serine/threonine kinase indispensable for protein biosynthesis and cell cycle advancement. Studies have demonstrated that rapamycin selectively fosters Treg expansion, and these cells exert robust protection against allograft rejection by suppressing the proliferation of syngeneic T cells in both in vitro and in vivo settings (240). Furthermore, rapamycin emerges as a viable candidate for ex vivo Treg expansion in T cell-driven pathologies, as it fails to hinder activation-induced cell death or CD4+ T cell proliferation under in vitro conditions (241). Rapamycin’s dual capacity to diminish T effector (Teff) cells while facilitating Treg differentiation renders it a valuable tool for developing innovative and safe cellular immunotherapeutic strategies (242).

5.1.3 Vasoactive intestinal peptide and statins

Vasoactive intestinal peptide (VIP) has been demonstrated to enhance Treg differentiation and proliferation within peripheral tissues and joints alike. VIP-induced Tregs have been shown to exert substantial suppressive effects and ameliorate chronic autoimmune conditions, establishing VIP as a promising therapeutic candidate for Treg-centric immunotherapy (243) (see Figure 5). Statins—commonly prescribed for their cardioprotective advantages—additionally exhibit pleiotropic immunomodulatory and anti-inflammatory activities that extend beyond their cholesterol-lowering effects. Their ability to selectively elevate Treg proportions in inflammatory foci and draining lymph nodes underscores their potential as Treg-targeted therapies for immune-mediated disorders (244, 245).

5.2 Biologicals

5.2.1 Interleukin-2

Interleukin-2 (IL-2) is a crucial proinflammatory cytokine that plays a major role in immune regulation and microbial defense, primarily through its effects on Tregs (246) (see Figure 5). The importance of IL-2 in Treg development and immune homeostasis is highlighted by the observation that IL-2-deficient mice exhibit uncontrolled T cell activation and autoimmunity (247). The IL-2 receptor (IL-2R), which can be either a high-affinity heterotrimeric complex (IL-2R α/CD25, IL-2Rβ, and γc chains) or a heterodimer (IL-2Rβ/CD122 and common γ (γc)/CD132 chains), is where IL-2 binds to produce its effects (248). Tregs constitutively express IL-2R α at high levels, making them more responsive to IL-2 signaling than other immune cells, including NK, Tconv, and innate lymphoid cells, which also express CD25, but to a lesser extent (249). This is because they constitutively express IL-2R α at high levels. IL-2 activates the signaling pathways that control Treg homeostasis and function, including STAT5/JAK1/3 and, to a lesser extent, PI3K/AKT/mTOR (250). IL-2 signaling suppresses the expression of immune checkpoint molecules on Tregs, including CTLA-4 and PD-1, while promoting Treg proliferation (251). Considering these characteristics, reestablishing immunological tolerance and preventing pathogenic autoimmune reactions can be achieved by focusing on the IL-2/Treg axis.

The FDA approved high-dose IL-2 therapy for metastatic cancers in 1992, but it’s extremely short half-life (less than 10 minutes) necessitated a high-dose bolus, which resulted in severe side effects like cytokine storm and vascular leak syndrome (252). Low-dose IL-2 (ld-IL-2) selectively expands Tregs with minimal activation of effector T cells; a multicenter trial demonstrated its broad immunoregulatory efficacy and safety across autoimmune diseases (253). In RA, ld-IL-2 combined with methotrexate increased circulating Tregs, improved immunological profiles, and alleviated clinical symptoms in a phase II study (254). Recent research has also shown that IL-2-based therapeutic approaches can effectively induce tolerance in animal models of food allergy and allergic asthma (255, 256). It is hypothesized that the selective expansion of Tregs via IL-2 administration may be beneficial for treating food allergies. The safe and well-tolerated nature of low-dose IL-2 has been confirmed in preclinical and clinical studies, paving the way for next-generation IL-2-based treatments (257).

5.2.2 TNF receptor 2 agonists

TNF-α, a pro-inflammatory cytokine, binds to two distinct receptors: TNFR1, which has a pro-inflammatory effect, and TNFR2, which promotes tissue regeneration and reduces inflammation (258) (see Figure 5). Tregs have been shown to express more TNFR2 than other T cell subsets, and their suppressive activity is directly correlated with TNFR2 expression (259). The molecular mechanisms underlying TNF-TNFR2 signaling in Tregs are complex and involve several key pathways. This signaling promotes the preferential expansion of Tregs by suppressing DNA methylation at the FoxP3 promoter (260). It also maintains an autocrine TNF-TNFR2 feedback loop that ensures Treg stability (258). Furthermore, it regulates kinase activities linked to TCR, JAK, MAPK, and PKC signaling pathways and modulates IL-17 expression in human Tregs (261). By promoting Treg function and proliferation, TNFR2 agonists may offer a novel therapeutic approach for treating various inflammatory and autoimmune conditions (262).

5.2.3 Intravenous immunoglobulin

Intravenous immunoglobulin (IVIg) is a sterile therapeutic preparation containing human IgG derived from a pool of healthy plasma donors (263) (see Figure 5). Administered at high doses (1 to 3 g/kg), IVIg has proven effective in treating a range of neurological and autoimmune conditions, including immunothrombocytopenia, Kawasaki disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, SLE, and dermatomyositis (264). IVIg infusions have been shown to modulate Tregs by enhancing the proliferation and potency of CD4⁺CD25⁺FoxP3⁺ T cells. This effect was demonstrated in NK cell-dependent EAE models. Following IVIg administration, patients with autoimmune rheumatic diseases also showed Treg expansion, which was linked to an increase in DCs cyclooxygenase-2-dependent prostaglandin E2 synthesis (265).

5.2.4 Tregitopes

Tregitopes are a novel class of peptides (15–26 amino acids in length) crucial for maintaining immune system control. They work by activating Tregs, which in turn produce suppressive cytokines like IL-10, TGF-β, and MCP-1 (266) (see Figure 5). This discovery has opened up the possibility of using Tregitopes as therapeutic targets for autoimmune diseases, including MS, SLE, and T1D (267). The primary mechanism by which Tregitopes induce immune tolerance is through their binding to MHC II molecules on the surface of APCs, which allows them to be presented to and activate Tregs (267). Furthermore, Tregitopes suppress the NF-κB pathway, which reduces the expression of costimulatory molecules and increases T cell anergy. They also decrease the expression of T effector (Teff) cytokines (IFN-γ, IL-5, and IL-6) while simultaneously increasing the production of Treg-associated cytokines (IL-10 and TGF-β). Tregitopes can also promote the conversion of Th2 cells into adaptive Tregs and Th1-like phenotypes by upregulating CTLA-4 expression (266).

Computational tools are used to identify Tregitopes within IgG, classifying peptides based on factors like their binding strength with MHC-II (267). Tregitopes have recently been used to treat autoimmune diseases primarily through Treg activation (268). For example, studies in T1D have explored using insulin-derived peptides to restore Treg activity. The C19-A3 peptide showed promise in a Phase I clinical trial, preserving islet cell function, whereas the B9–23 peptide resulted in anaphylactic reactions due to its unpredictable interaction with MHC (269). A safer approach for treating MS involved the co-administration of IVIg-derived Tregitopes with the MOG35–55 epitope, as this combination showed significant anti-inflammatory properties in EAE models (266). More recently, Bemani et al. (270) used bioinformatics to create a multi-epitope vaccine to increase tolerance in myelin-specific T cells, which could slow MS progression and prevent relapses. This vaccine includes an anti-DEC205 single-chain variable fragment (scFv) antibody, a multi-epitope section with MS-associated antigens and Tregitopes, and VIP. Additionally, Edratide, a human peptide not classified as a Tregitope but with a similar function, has been shown to reduce SLE symptoms by modulating TGF-β, FoxP3, and inflammatory cytokines like IFN-γ and IL-1β, thereby restoring immune homeostasis (271, 272). Despite their promise, Tregitope-based therapies face several challenges, including the need to optimize drug formulations and delivery methods to specifically target Tregs. More preclinical and clinical research is required to determine the best dosages and delivery systems (266). In a study on a mouse model of allergic airway disease (AAD), Marieme Dembele et al. (273) found that administering mouse and human IgG Tregitopes decreased lung inflammation and attenuated allergen-induced airway hyperresponsiveness. Similar to IVIg, human IgG Tregitopes reduced allergic airway disease in mice. Tregitope treatment increased Helios⁺ Tregs in mediastinal lymph nodes, and Tregs from treated mice showed enhanced suppression compared to controls. The antigen-specific nature of the Treg response was confirmed when transferring Tregs from treated mice to allergen-sensitized mice; only Tregs from mice exposed to the same allergen were able to reduce AAD (273).

In conclusion, the combination of Tregitopes and allergens offers a natural immune tolerance mechanism that may induce highly suppressive and antigen-specific Helios⁺ Tregs. This form of immunomodulation holds promise as a new treatment for human reactive airway disease and other allergic disorders.

5.3 Treg cell therapies

5.3.1 Polyclonal Tregs therapy

Treg cell therapy aims to restore immune tolerance by directly increasing the number of Tregs, especially in autoimmune disorders where autoantigen-specific Treg function is compromised (274) (see Figure 5). The effectiveness of this strategy relies on the ability of Tregs to maintain their suppressive function and stability over time while retaining antigen specificity (275).

In polyclonal Treg therapy, CD4⁺CD25^high Tregs are isolated from the patient’s peripheral blood or inflammatory sites, expanded in vitro, and then re-infused. When stimulated with anti-CD3/CD28 monoclonal antibody-coated beads and high doses of IL-2, human Tregs can proliferate up to 40,000-fold in vitro. These expanded cells exhibit stronger suppressive function than freshly isolated Tregs while maintaining their expression of CD25, FoxP3, and lymph node homing receptors (276). However, the expansion and infusion of Tregs present several challenges: (i) the protocol is labor-intensive for each patient; (ii) it requires careful monitoring to ensure the purity and antigen specificity of the Tregs to prevent the proliferation of self-reactive Teff cells or Tregs with incorrect specificity; and (iii) there is a potential risk of infection or transformation during the ex vivo expansion process (277). After infusion, the injected Tregs peak in the bloodstream within the first two weeks, then gradually decline, but can remain detectable for up to a year (278).

Polyclonal Treg therapy is currently being investigated in clinical trials for conditions like T1D, COVID-19, cutaneous pemphigus, autoimmune hepatitis (AIH), and SLE aming to optimize treatment by determining the ideal dosage, number of doses, and timing between infusions (279). Better therapeutic outcomes and enhanced Treg suppressive capacity are expected when Treg therapy is combined with other treatments that increase Treg numbers and function, such as rapamycin, TNFR2 agonists, IL-2, and IL-10 (275). There is still great potential in this field, particularly in developing methods to improve Treg resistance and persistence for more durable and effective immunomodulation.

5.3.2 Engineered antigen-specific TCR-Treg therapy

Incorporating an autoantigen-specific T-cell receptor (TCR) can enhance Treg therapy by focusing the cells’ response on a particular autoantigen, thereby avoiding the risk of widespread immune suppression (280) (see Figure 5). This approach involves genetically modifying Tregs ex vivo using retroviral or lentiviral transduction methods to express a high-affinity, autoantigen-specific TCR. These modified TCR-Tregs can then be expanded and re-infused into patients to regulate disease-specific autoimmune responses (281).

Recent studies have demonstrated that combining TCR knock-in with FOXP3 stabilization or engineered IL-2–responsive modules markedly improve Treg stability, persistence, and antigen-dependent activation. A representative example is GNTI-122, a dual-edited islet-specific TCR-Treg product incorporating FOXP3 reinforcement and a chemically inducible IL-2 signaling cassette, which showed robust antigen-specific activation, pancreatic homing, and suppression of diabetogenic responses in preclinical models of type 1 diabetes (T1D) (282).

Antigen-specific TCR-Tregs have been most actively developed for organ-specific autoimmune diseases with well-defined autoantigens. In multiple sclerosis (MS), myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) remain principal targets, and engineered myelin-specific TCR-Tregs suppress pathogenic effector T-cell responses and ameliorate disease in experimental autoimmune encephalomyelitis models (277, 283). In T1D, insulin, glutamic acid decarboxylase (GAD), IGRP, and hybrid insulin peptides have been used to generate islet-reactive TCR-Tregs capable of controlling autoreactive T-cell expansion and limiting insulitis (277, 282). These advances underscore critical translational considerations, including stringent TCR specificity screening, HLA restriction, and incorporation of persistence/survival modules to ensure durable functionality in inflammatory microenvironments (283).

Beyond autoimmunity, antigen-specific regulatory strategies are rapidly emerging in allergic diseases, in which allergen-specific tolerance is central to long-term disease control. Allergen-specific immunotherapy (AIT) naturally induces allergen-directed FOXP3+ Tregs, and engineered TCR-Tregs are now being explored to mimic and enhance this pathway. Preclinical studies suggest that allergen-specific regulatory cells can suppress IgE production, Th2 cytokines, and effector-cell activation in models of allergic rhinitis and asthma, although challenges remain regarding allergen heterogeneity, mucosal trafficking, and long-term Treg stability (284). Contemporary reviews highlight that integrating antigen specificity with engineered stability modules represents a promising avenue to achieve durable immune tolerance across both autoimmune and allergic contexts (275, 285).

5.3.3 Chimeric Treg therapy

Chimeric Treg therapy is an advanced technique designed to enhance the antigen specificity and functionality of Tregs. This strategy involves the genetic modification of Tregs to express specific proteins on their surface, such as MHC class II-restricted TCRs (286) (see Figure 5). In theory, any desired protein can be transduced onto a Treg cell. Numerous innovatively designed chimeric Tregs have already shown their efficacy in preclinical models of autoimmune diseases. In one MS mouse model, for example, the cytoplasmic tail of CD3ζ was associated with a myelin peptide-MHC class II complex. Treg effectiveness was at least ten times increased as a result. The enhancement was further regulated by co-transduction of FoxP3 and the peptide-MHC class II complex onto Tconv cells (287). Furthermore, it has been demonstrated that Tregs retained their antigen-specific suppressive activity when MHC class I-restricted TCRs were transduced onto them (288). This implies that TCRs from non-Treg cells, like CD8⁺ CD4⁺ T cells or Tconv cells, could be successfully transferred onto Tregs in order to reroute their regulatory function (289).

5.3.4 Chimeric antigen receptor-Tregs therapy

Chimeric Antigen Receptor (CAR)-Tregs are a specialized type of chimeric Treg designed to directly target specific tissue autoantigens without relying on MHC restriction. The CAR molecule consists of an extracellular antigen-recognition domain, a hinge, a transmembrane region, and an intracellular signaling domain that is part of the Treg signaling machinery (290) (see Figure 5). CAR-Tregs are engineered to migrate to and attach to tissue-specific autoantigens at the site of autoimmunity, thereby concentrating their suppressive effects (291). However, a potential drawback is that if the target autoantigen is present in healthy tissues, widespread activation of CAR-Tregs could occur, leading to undesirable systemic immune suppression (Table 3).

Table 3

Table 3. Human studies of CAR-T cell treatment for autoimmune diseases.

In contrast to TCR-Tregs, CAR-Tregs have a higher affinity for their corresponding antigen, circumvent MHC restriction, and are less reliant on IL-2. These characteristics set CAR technologies apart from TCR engineering. For them to effectively stimulate Tregs, the target cell must have at least 100 target autoantigens. By contrast, the TCR can activate the Treg population with just one peptide-MHC complex (92). Since TCRs are normally detected at a level of ~50,000/cell, while CARs are present in greater quantities, surpassing 50,000/cell, this difference should be taken into account. Immunoreceptor tyrosine-based activation motifs (ITAMs) and tyrosines are more abundant in the intracellular signaling domain of CAR-Tregs than in TCR-Tregs, which results in a more potent activation and a greater signaling capacity. TCRs are easier to express because of their heterodimeric structure, whereas CAR is a monomeric protein. Co-stimulatory receptors like CD4 and CD28 are necessary for TCR activation. Nevertheless, CAR does not require these coreceptors for activation (292).

The CAR-Treg approach has shown promise in preclinical models. Recently, a mouse model of ovalbumin (OVA) allergy was used to assess the CAR approach. The CAR Treg cell in this study was made up of OVA connected to the CD28-CD3ζ transmembrane and signal transduction domains (293). In the mice model, this CAR Treg cell therapy reduced the anaphylactic reaction brought on by intraperitoneal OVA injection (293). Treg cells transduced with Bet v 1-specific TCR inhibited the production of cytokines and the proliferation of allergen-specific effector T cells in cell culture (294).

The use of allogeneic CAR-T cells from “healthy donors” offers a rapid, scalable, and cost-effective method for producing large quantities of cells that can be cryopreserved and made readily available for patients. However, a major challenge is that the host immune system may reject them, or they could cause graft-versus-host disease (GvHD) (295). Consequently, novel approaches are being explored to generate “off-the-shelf” universal CAR-T cells from healthy allogeneic donors. One such approach involves gene editing using platforms like clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 (296).

6 Challenges in the clinical translation of Treg-based therapies for allergic rhinitis and autoimmune diseases

Despite strong evidence from how they work and promising early lab results, the use of Treg-based treatments for allergic rhinitis (AR) and autoimmune diseases in clinics is held back by several unsolved problems. These challenges cover Treg production, stability, tissue targeting, safety, clinical plan design, lab model limits, and large-scale production.

Getting enough pure FoxP3⁺CD25^high Tregs for treatment is a major hurdle. Therapy usually needs 10⁶–10⁸ cells per kilogram of body weight, but growing Tregs outside the body often leads to mixing with harmful effector T cells. Strict purification reduces the number of Tregs obtained—this is even worse for autoimmune patients, who often start with too few Tregs. Another problem is functional instability: inflamed environments rich in certain proteins (IL-4/IL-13 in AR and IL-6/TNF-α in autoimmune diseases) can lower FoxP3 levels and turn Tregs into effector-like or even harmful cells. While gene-editing and protein-based treatments can improve stability, concerns about unintended effects, different patient responses, and long-term effectiveness remain.

Beyond production challenges, targeted delivery and tissue homing pose significant troubles. Giving Tregs through the veins makes most of them get stuck in non-target organs like the liver and spleen, so too few reach the diseased areas (e.g., nasal lining in AR or joints/kidneys in autoimmune diseases). Local delivery also has issues: mucus barriers and damaged nasal lining in AR stop Tregs from staying alive, while inflamed blood vessels and changed protein signals in autoimmune tissues block Tregs from entering. The lack of good delivery tools—such as tissue-targeting materials, protein-guided carriers, or tiny particle delivery systems—further limits precise homing.

Safety remains a critical concern for Treg therapy. It has inherent risks of too much immune suppression, which may increase infection risk or weaken the nasal lining’s defense against AR. Other safety issues include genetic changes when growing cells outside the body, the risk that donated Tregs trigger an immune response, and unknown long-term effects like abnormal immune tolerance or shifts in overall immune function. Importantly, most current clinical trials don’t follow patients for long, so we don’t fully understand how long transferred Tregs last, how well they work over time, or their long-term safety.

Clinical protocol design also presents significant uncertainties. Key clinical details—including the best dose, delivery method, treatment frequency, and length—are not well defined. Effective doses seem to differ by disease and disease stage, and the range between not working and suppressing the immune system too much is narrow. Local nasal delivery for AR (e.g., nebulized or nose drops) is still experimental. Furthermore, combining Treg therapy with other treatments—such as steroids, JAK inhibitors, allergen immunotherapy, or antigen-specific tolerance induction—has not been fully optimized or standardized.

Compounding these issues are gaps in preclinical modeling and biomarker development. Common mouse models (e.g., OVA-induced AR or collagen-induced arthritis) don’t fully reflect human immune differences, Treg stability, or chronic disease progression. As a result, lab results often don’t predict how well treatments work in humans. The lack of reliable markers to select patients, monitor Treg function in real time, and spot early safety issues also makes it hard to standardize clinical outcomes and accurately assess treatment effects.

Finally, technical and industrial barriers hinder widespread translation. Producing large amounts of clinical-grade Tregs is technically difficult. Growing protocols rely on complex protein mixes and stimulation systems that vary between labs, making standardization and quality control hard. Costs for making patient-specific Tregs are very high, while using donated Tregs raises issues of immune compatibility and unknown long-term survival. Together, these technical and economic barriers limit wider clinical use.

7 Conclusion

Tregs are pivotal in sustaining immune homeostasis and peripheral tolerance. Deviations in their abundance or functionality are intimately linked to the pathogenesis of autoimmune and allergic diseases. Although these disorders present with disparate clinical features, they converge on a fundamental defect in Treg-orchestrated tolerance mechanisms, positioning Tregs as a crucial nexus between these principal immunological categories. Over recent years, diverse therapeutic modalities have demonstrated encouraging efficacy in reinstating immune equilibrium, as evidenced by preclinical models and clinical investigations. These progressions indicate that precision Treg-directed therapies are evolving into feasible clinical options. Nevertheless, Treg-based interventions encounter formidable challenges, including the intrinsic heterogeneity and plasticity of Tregs, the erosive effects of inflammatory microenvironments, and the risk of Treg transdifferentiation into proinflammatory states amid chronic inflammation. Prospective inquiries should prioritize delineating the molecular underpinnings of Foxp3 stability and Treg adaptability to enable the formulation of tissue- and antigen-tailored precision strategies. Integrating surface biomarker profiling, multi-omics surveillance, and translational methodologies offers substantial promise for realizing individualized immune restoration and enduring tolerance. In essence, Tregs not only constitute a central pathological fulcrum in autoimmune and allergic afflictions but also embody a prime avenue for attaining meticulous immune recalibration and sustained tolerance prospectively.

Author contributions

W-WX: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Writing – original draft, Validation. J-BH: Conceptualization, Data curation, Formal Analysis, Investigation, Writing – original draft. Y-CZ: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing. J-YY: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Writing – original draft. J-XF: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Writing – original draft. X-HS: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft. LT: Conceptualization, Data curation, Investigation, Methodology, Writing – original draft. X-HZ: Conceptualization, Data curation, Investigation, Methodology, Software, Supervision, Writing – original draft. S-QQ: Funding acquisition, Project administration, Resources, Supervision, Visualization, Writing – review & editing. M-ZZ: Formal Analysis, Funding acquisition, Project administration, Resources, Supervision, Writing – review & editing. B-HC: Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing – review & editing. H-TZ: Funding acquisition, Project administration, Resources, Supervision, Writing – review & editing, Data curation, Validation, Visualization.

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work was supported by grants from the Natural Science Foundation of China (Nos. 82474586 and 82204743), Guangdong Basic and Applied Basic Research Foundation (2023A1515012207 and 2022A1515111103), Shenzhen Innovation of Science and Technology Commission (No. JCYJ20240813113359046, JCYJ20210324142207019, and JCYJ20220531091602005), Longgang District Science and Technology Plan (No. LGKCYLWS2022003, LGKCYLWS2022010, LGKCYLWS2022031, LWGJ2023-089, LWGJ2023-142), and Shenzhen Key Medical Discipline Construction Fund (No. SZXK039). Longgang Medical Discipline Construction Fund (Key Medical Disciplines in Longgang District). Wu Jieping Medical Foundation (320.6750.2025-6-100).

Conflict of interest

The authors declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Glossary

AAD: allergic airway disease

AD: atopic dermatitis

AHR: aryl hydrocarbon receptor

AIG: autoimmune gastritis

AIH: autoimmune hepatitis

AIT: allergen immunotherapy

APCs: antigen-presenting cells AR, allergic rhinitis

Areg: amphiregulin

BALF: bronchoalveolar lavage fluid

Bcl-2: B-cell lymphoma 2

BCMA: B cell maturation antigen

CAART: chimeric antigen receptor-T cell therapy

CAR: chimeric antigen receptor

CB4: Coxsackievirus B4

CCR: C-C Chemokine Receptor

CD: cluster of differentiation

CKD: chronic kidney disease

CNS: central nervous system

CO: carbon monoxide

COVID-19: corona virus disease 2019

CpG: cytosine-phosphate-Guanine

CRISPR: clustered regularly interspaced short palindromic repeats

CRTH2: chemoattractant receptor-homologous molecule expressed on Th2 cells

CTLA-4: cytotoxic T-lymphocyte-associated protein 4

DCs: dendritic cells

DNA: deoxyribonucleic acid

Dsg3: desmoglein 3

EAE: experimental autoimmune encephalomyelitis

EAT: experimental autoimmune thyroiditis

FA: food allergy

FcεRI: Fc epsilon receptor I

FDA: food and drug administration

FHA: filamentous hemagglutinin

FKBP12: FK506-binding protein

FoxP3: forkhead box P3

GATA3: GATA binding protein 3

GBM: glomerular basement membrane

GFP: green fluorescent protein

GM-CSF: granulocyte-macrophage colony-stimulating factor

GvHD: graft-versus-host disease

HDAC: Histone Deacetylase

HT: Hashimoto’s thyroiditis

IBD: inflammatory bowel disease

IDO: indoleamine 2,3-dioxygenase

IFN: interferon

IgE: immunoglobulin E

IgG: Immunoglobulin G

IL: interleukin

ILCs: innate lymphoid cells

ILT3⁺: immunoglobulin-like transcript 3-positive

IPEX: immunodeficiency, polyendocrinopathy, and enteropathy X-linked syndrome

ITAMs: immunoreceptor tyrosine-based activation motifs

ITP: immune thrombocytopenic purpura

iTr35: inducible regulatory T cells 35

iTregs: induced Tregs

IVIg: Intravenous immunoglobulin

JAG1: Jagged 1

JAK: Janus kinase

JIA: juvenile idiopathic arthritis

MAPK: mitogen-activated protein kinase

MBP: myelin basic protein

MHC: major histocompatibility complex

MK: midkine

MLN: mesenteric lymph nodes

MOG: myelin oligodendrocyte glycoprotein

MOG: myelin oligodendrocyte glycoprotein

MPV: metapneumovirus

MS: multiple sclerosis

mTOR: mammalian target of rapamycin

NFAT1: nuclear factor of activated T cells 1

NF-κB: nuclear factor-kappa B

NKs: natural killer cells

NMOSD: neuromyelitis optica spectrum disorder

NO2: nitrogen dioxide

NOD: non-obese diabetic

nTregs: natural Tregs

OVA: ovalbumin

PAHs: polycyclic aromatic hydrocarbons

PBMCs: peripheral blood mononuclear cells

PD: parkinson’s disease

PD1: programmed death-1

pDCs: plasmacytoid dendritic cells

PKC: protein kinase C

PM: particulate matter

PPAR-γ: peroxisome proliferator-activated receptor-gamma

pSS: primary Sjögren’s syndrome

RA: rheumatoid arthritis

RORα: receptor-related orphan receptor α

RORγt: retinoid-related orphan receptor gamma T

SCFAs: short-chain fatty acids

scFv: single-chain variable fragment

SLE: systemic lupus erythematosus

SMAD: Sma and mad related proteins

STAT: signal transducer and activator of transcription

T1D: type 1 diabetes

Tconv: conventional T cells

TCR: T Cell Receptor

TCs: Thetis cells

Teff: T effector cells

Tfh: follicular T helper (Tfh) cells

Tfr: follicular regulatory T cells

TGF-β: transforming growth factor-beta

Th2: T helper 2 cell

TLR: toll-like receptor

TNF: tumor necrosis factor

TNFR: tumor necrosis factor receptor

Tr1: type 1 regulatory T cell

Tregs: regulatory T cells

TSLPR: thymic stromal lymphopoietin receptor

VIP: vasoactive intestinal peptide

WAS: Wiskott-Aldrich syndrome.

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