Abstract
Regulatory T cells (Tregs) are pivotal immune modulators essential for maintaining immune homeostasis and preventing aberrant immune responses. In recent years, Treg-based therapies have emerged as a promising strategy for treating a variety of non-malignant diseases, including autoimmune disorders, transplantation-related complications, and allergic conditions. This review provides a comprehensive overview of the discovery and evolution of Tregs, detailing their immunoregulatory mechanisms that underpin their therapeutic potential. We systematically evaluate current clinical applications of Treg therapy in diverse non-tumor pathologies, highlighting both the efficacy and safety outcomes reported in ongoing clinical trials. Additionally, the review addresses the challenges faced in translating Treg therapies from bench to bedside, such as cell stability, expansion methodologies, and functional heterogeneity. Finally, we explore future directions in Treg research, including innovative therapeutic approaches, advances in gene engineering technologies, and improvements in cell expansion techniques, all aimed at enhancing the clinical translation and therapeutic efficacy of Treg-based interventions. This article aims to provide a thorough theoretical foundation and practical guidance to advance the application of Treg therapy in non-malignant diseases.
1 Introduction
Regulatory T cells (Tregs) constitute a specialized subset of CD4+ T lymphocytes characterized primarily by the expression of the transcription factor forkhead box protein P3 (Foxp3), which is indispensable for their development and suppressive function. These cells serve as pivotal mediators of immune homeostasis, orchestrating the balance between immune activation and tolerance to self-antigens, thereby preventing the onset of autoimmune diseases and maintaining peripheral tolerance. The immunosuppressive capacity of Tregs extends beyond the containment of autoreactive T cells; they also play crucial roles in modulating immune responses to commensal microbiota, allergens, and tissue-specific antigens, ensuring the fine-tuning of immune reactivity in diverse physiological contexts (1, 2). The significance of Tregs in immune regulation is underscored by the observation that their quantitative or functional deficiencies are implicated in a broad spectrum of immunopathologies, including autoimmune disorders, allergic diseases, and chronic inflammatory conditions. In this light, Tregs have emerged as a promising cellular target for therapeutic interventions aimed at restoring immune tolerance without compromising global immune competence.
The pathogenesis of non-tumor diseases such as autoimmune disorders, allergic inflammation, and chronic inflammatory diseases is often characterized by a breakdown in immune tolerance mechanisms, leading to aberrant activation of effector immune cells against self or innocuous antigens. This immune dysregulation is frequently associated with defects in Treg number, phenotype, or suppressive function, which collectively contribute to the perpetuation of pathological immune responses (3, 4). For instance, in autoimmune diseases like type 1 diabetes (T1D), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), the failure to adequately control autoreactive T cells by Tregs results in tissue-specific damage and chronic inflammation (5, 6). Similarly, in allergic diseases, subversion of Treg function leads to unrestrained type 2 immune responses and tissue pathology (5). These insights highlight the therapeutic potential of strategies aimed at enhancing Treg-mediated immune regulation to re-establish tolerance and ameliorate disease.
Recent years have witnessed remarkable advancements in the understanding of Treg biology, from their molecular development and tissue-specific adaptations to their functional specialization in various non-lymphoid organs. Tissue-resident Tregs exhibit distinct transcriptional profiles and antigen specificities that enable them to maintain local immune homeostasis and contribute to tissue repair and regeneration beyond their canonical immunosuppressive roles (7, 8). Moreover, innovative approaches to modulate or harness Tregs, including ex vivo expansion, induction of antigen-specific Tregs, and pharmacological conversion of conventional T cells into Tregs, have shown promising results in preclinical models and early-phase clinical trials targeting non-tumor diseases (9, 10). For example, immune-homeostatic microparticles designed to induce apoptosis of activated T cells and promote Treg differentiation have demonstrated efficacy in mouse models of autoimmunity (11). Additionally, novel small molecules that convert memory CD4+ T cells into suppressive Foxp3+ Tregs via modulation of signaling pathways offer potential for inducing immune tolerance (11). These therapeutic innovations underscore the translational momentum from foundational immunology towards clinical application.
Given the expanding landscape of Treg research and its translational implications, there is an urgent need for comprehensive and systematic reviews that integrate the latest biological insights, therapeutic strategies, and clinical outcomes related to Treg therapy in non-tumor diseases. Such analyses are critical to delineate the current state of the art, identify challenges such as Treg stability, antigen specificity, and functional heterogeneity, and forecast future directions including combination therapies and precision immunomodulation. This review aims to provide an exhaustive synthesis of the biological characteristics of Tregs, their immunoregulatory mechanisms, and their clinical applications in non-tumor diseases. By evaluating existing clinical trial data and emerging therapeutic modalities, we seek to offer a nuanced perspective on the prospects of Treg-based interventions and outline strategic avenues for enhancing their efficacy and safety in diverse pathological contexts.
2 Regulatory T cells: biology, mechanisms, and therapeutic applications
2.1 Biological characteristics of treg cells
2.1.1 Historical milestones
The discovery of regulatory T (Treg) cells marked a pivotal moment in immunology, fundamentally reshaping our understanding of immune tolerance and autoimmunity. Initially identified as a subset of CD4+ T cells expressing high levels of CD25, the interleukin-2 receptor alpha chain, Tregs were characterized by their unique ability to suppress immune responses and maintain self-tolerance. The landmark identification of the transcription factor Foxp3 as a lineage-defining marker of Treg cells was crucial, as Foxp3 expression was shown to be indispensable for Treg development and function. Early experimental work demonstrated that mutations in Foxp3 led to severe autoimmune syndromes, underscoring the essential role of Tregs in immune regulation. Key experiments, such as adoptive transfer studies in mice, established that Tregs could prevent autoimmune disease by suppressing autoreactive T cells. These foundational studies firmly positioned Tregs as central players in immune homeostasis, highlighting their suppressive capacity through cell contact-dependent mechanisms and cytokine secretion. The identification of surface markers CD4, CD25, and intracellular Foxp3 provided tools for isolating and studying Tregs, facilitating subsequent research into their biology and therapeutic potential. More recently, the field has undergone a conceptual shift from viewing Tregs solely as immunosuppressive cells to recognizing them as tissue-integral regulators with context-specific functions extending far beyond canonical immune suppression, including roles in tissue repair, metabolic homeostasis, and stem cell niche maintenance (12, 13). Collectively, these milestones laid the groundwork for recognizing Treg cells as the core regulators of immune tolerance and opened avenues for their clinical application in autoimmunity, transplantation, and beyond (14, 15).
2.1.2 Cell biology and subtype evolution
Regulatory T cells (Tregs) exhibit considerable heterogeneity, classified primarily into thymus-derived natural Tregs (nTregs or tTregs) and peripherally induced Tregs (iTregs or pTregs). nTregs develop in the thymus during T cell maturation and are characterized by stable expression of Foxp3, which is critical for their suppressive function and lineage stability. In contrast, iTregs arise from conventional CD4+ T cells in peripheral tissues upon antigenic stimulation under tolerogenic conditions, such as in the presence of transforming growth factor-beta (TGF-β). Foxp3 acts as the master transcription factor orchestrating Treg development, function, and maintenance by regulating gene expression programs that confer suppressive capacity. The expression of Foxp3 is tightly controlled by epigenetic modifications and post-translational modifications, ensuring Treg lineage stability. The surface markers, tissue distribution patterns, and functional properties of major Treg subsets are summarized in Table 1.
Table 1
| Treg subset | Core markers | Additional key markers | Primary tissue location | Key functional features |
|---|---|---|---|---|
| Classification by developmental origin | ||||
| Thymic Tregs (tTregs/nTregs) | CD4+CD25+Foxp3+ | Helios+ (enriched), Nrp-1+ (in mice), TSDR demethylated | Thymus, secondary lymphoid organs | Stable suppressive function; self-antigen tolerance; stable Foxp3 expression |
| Induced Tregs (iTregs/pTregs) | CD4+CD25+Foxp3+ | Helios-/low (enriched), Nrp-1-/low (in mice) | Peripheral tissues, mucosal sites | Induced by TGF-β in periphery; tolerance to non-self antigens including commensal microbiota and dietary antigens |
| Classification by activation/functional state | ||||
| Central Tregs (cTregs) | CD4+CD25+Foxp3+ | CCR7+, CD62L+, CD44low | Secondary lymphoid organs (lymph nodes, spleen) | Quiescent state; lymphoid tissue homing; IL-2 dependent survival |
| Effector Tregs (eTregs) | CD4+CD25+Foxp3+ | CD44hi, CD62Llow, ICOS+, KLRG1+ | Non-lymphoid peripheral tissues | Enhanced suppressive capacity; tissue migration; activated phenotype |
| Classification by transcriptional specialization | ||||
| Th1/Th2/Th17-like Tregs | CD4+CD25+Foxp3+ | T-bet+/CXCR3+ (Th1-like); IRF4+/GATA3+ (Th2-like); RORγt+/CCR6+ (Th17-like) | Sites corresponding to respective Th inflammation | Co-expression of lineage-defining transcription factors; preferential suppression of matched Th responses |
| Classification by anatomical location | ||||
| Colonic/Intestinal Tregs | CD4+CD25+Foxp3+ | RORγt+ (subset), IL-10+ | Colon, small intestine lamina propria | Microbiota-induced tolerance; mucosal homeostasis |
| Follicular Regulatory T cells (Tfr) | CD4+CD25+Foxp3+ | Bcl-6+, CXCR5+, PD-1+ | Germinal centers, B cell follicles | Regulation of germinal center reactions; control of Tfh and B cell responses |
Summary of major Treg populations: markers, tissue distribution, and functional features.
Bcl-6, B-cell lymphoma 6; CCR6, C-C chemokine receptor type 6; CCR7, C-C chemokine receptor type 7; CD, cluster of differentiation; CD62L, L-selectin; cTreg, central regulatory T cell; CXCR3, C-X-C motif chemokine receptor 3; CXCR5, C-X-C motif chemokine receptor 5; eTreg, effector regulatory T cell; Foxp3, forkhead box P3; GATA3, GATA binding protein 3; ICOS, inducible T cell costimulator; IL-2, interleukin-2; IL-10, interleukin-10; IRF4, interferon regulatory factor 4; iTreg, induced regulatory T cell; KLRG1, killer cell lectin-like receptor G1; Nrp-1, neuropilin-1; nTreg, natural regulatory T cell; PD-1, programmed cell death protein 1; pTreg, peripheral regulatory T cell; RORγt, retinoic acid receptor-related orphan receptor gamma t; T-bet, T-box transcription factor TBX21; Tfh, T follicular helper cell; Tfr, follicular regulatory T cell; TGF-β, transforming growth factor-beta; Th, T helper; TSDR, Treg-specific demethylated region; tTreg, thymic regulatory T cell.
The concept of “tissue adaptation” has emerged as a central paradigm: upon entry into non-lymphoid tissues, Tregs undergo transcriptional reprogramming driven by tissue-specific transcription factors (e.g., peroxisome proliferator-activated receptor gamma (PPARγ) in adipose tissue, B lymphocyte-induced maturation protein 1 (Blimp-1) in barrier tissues, cellular musculoaponeurotic fibrosarcoma oncogene homolog (c-Maf) in gut), local metabolites (short-chain fatty acids, retinoic acid, bile acids), and stromal cell-derived signals (16, 17). This adaptation involves not only acquisition of tissue-homing receptors but also fundamental rewiring of metabolic and effector programs. Notably, tissue Tregs often exhibit reduced TCR signaling requirements for maintenance compared to lymphoid Tregs, instead relying more heavily on cytokine signals, such as interleukin (IL)-2 and IL-33, as well as metabolic inputs (18, 19). Different Treg subtypes display tissue-specific distribution and functional specialization; for instance, tissue-resident Tregs in non-lymphoid organs like adipose tissue, skin, and intestine exhibit unique transcriptomic profiles and contribute to local homeostasis beyond immune suppression, including tissue repair and metabolic regulation. Moreover, Treg subsets vary in their expression of surface molecules and cytokine profiles, reflecting their adaptability to diverse immunological contexts. The dynamic interplay between nTregs and iTregs, along with their phenotypic and functional plasticity, underlies the complexity of immune regulation mediated by Tregs in health and disease (15, 20, 21).
2.1.3 Mechanisms of action
Tregs employ a context-dependent repertoire of suppressive mechanisms to maintain immune homeostasis (Figure 1). Core pathways include metabolic control through high CD25 expression, enabling IL-2 sequestration and limiting conventional T cell proliferation in environments where IL-2 availability fluctuates; cytotoxic T lymphocyte-associated antigen (CTLA-4)–mediated suppression that reprograms antigen-presenting cells to dampen costimulation; and ectonucleotidase activity via CD39 and CD73 that convert pro-inflammatory ATP to anti-inflammatory adenosine, shaping a tolerogenic milieu in barrier tissues such as gut and skin (22, 23). Additional soluble mediators—TGF-β, IL-35, IL-10, and fibrinogen like protein 2 (FGL2)—broadly dampen effector functions and promote regulatory phenotypes. Tregs also possess granzyme–perforin–dependent cytotoxicity that can selectively eliminate overactive or cytotoxic targets, contributing to tolerance in transplantation and autoimmunity (24). Importantly, these mechanisms show tissue- and state-specific emphasis: in the gut, TGF-β and retinoic acid foster iTreg induction and stability with CD39/CD73-adenosine signaling playing a pivotal anti-inflammatory role; in adipose tissue, IL-10 and metabolic adaptations enable suppression of pro-inflammatory macrophages and maintenance of insulin sensitivity; in barrier organs, Tregs cooperate with local cues to sustain barrier integrity and promote repair; and in inflamed joints, CTLA-4 and IL-2–driven expansion must contend with inflammatory milieus that can undermine FOXP3 stability and functional capacity (25, 26). In autoimmune inflammation, persistent inflammatory cues erode this regulatory network: pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) destabilize FOXP3 signaling, enhanced APC costimulation heights Teff reactivity, and tissue-specific constraints create niches where suppression falters (23, 27–30). These dynamics explain why Treg-based therapies may require organ- or disease-specific tuning and combination strategies, including antigen-specific Tregs and localized delivery, to sustain tolerance. A further dimension is Treg stability and lineage plasticity: inflammatory milieus can destabilize FOXP3 via epigenetic and metabolic perturbations, driving ex-Tregs or Th17-like conversions that compromise tolerance. Therapeutically, stabilizing FOXP3 through sustained IL-2 signaling, metabolic modulation, and epigenetic targeting—alongside engineering approaches such as CAR- or TCR-Tregs with built-in stability safeguards—constitutes a critical priority. In translational terms, these insights imply that Treg products should be tailored to tissue context, disease stage, and concomitant inflammatory pathways, with combination regimens and robust immunomonitoring to guide dosing and delivery.
Figure 1
2.1.4 Stability and lineage plasticity in inflammation
Treg stability and lineage plasticity are central to the success of Treg-based therapies in autoimmune and inflammatory diseases (31). Inflammatory cues can destabilize FOXP3 expression through epigenetic and transcriptional mechanisms, promoting ex-Tregs or Th17-like reprogramming with direct implications for clinical outcomes. FOXP3 stability relies on TSDR demethylation and sustained FOXP3 transcriptional networks driven by IL-2–STAT5 signaling; inflammatory signals such as IL-6–STAT3 and IL-1β can shift transcriptional programs toward Th17 features, while metabolic reprogramming from oxidative phosphorylation toward glycolysis further undermines regulatory identity (32, 33). Consequently, biomarkers of stability (FOXP3 levels, TSDR methylation, metabolic state, cytokine signaling profiles) become essential for patient stratification and real-time monitoring (34). Therapeutic strategies to bolster stability include persistent low-dose IL-2 to sustain STAT5 activity, localized delivery and co-treatments that curb pro-inflammatory cues (e.g., retinoic acid signaling, TGF-β–mediated regulation), and epigenetic or metabolic interventions to preserve TSDR demethylation and regulatory metabolism (35). Engineered Tregs also require designs that maintain FOXP3 expression in inflammatory environments and resist circuit-driven drift (36). Clinically, stability-focused regimens should be disease- and organ-specific, balancing durable tolerance with preservation of host defense, and should be coupled with adaptive immunomonitoring and flexible dosing.
2.2 Clinical applications of treg cell therapy
2.2.1 Autoimmune diseases
In autoimmune diseases such as T1D, RA, and multiple sclerosis (MS), dysfunction or deficiency of Tregs contributes to the breakdown of immune tolerance, leading to tissue-specific autoimmunity (4, 37). Typical clinical applications of Treg cell therapy in autoimmune diseases are summarized in Table 2. The therapeutic application of Tregs aims to restore this balance by either expanding endogenous Tregs or adoptively transferring ex vivo expanded Tregs to suppress pathogenic effector T cells (38) (Figure 2).
Table 2
| Disease category | Specific indication | Therapy type | Development stage | Key endpoints/outcomes | Major limitations | Representative trials |
|---|---|---|---|---|---|---|
| Type 1 Diabetes | Recent-onset T1D | Autologous polyclonal Tregs (monotherapy) | Phase I/II | Safe in children/adolescents; No significant C-peptide preservation; Inverse correlation between expansion fold and efficacy | Limited in vivo persistence; Lack of functional durability; Small sample sizes (n=12-14); Short follow-up (1-2 years) | NCT01210664; NCT02691247 |
| Recent-onset T1D | Tregs + anti-CD20 (Rituximab) | Phase I/II | Attenuated β-cell loss; Preserved C-peptide levels; Reduced insulin requirements; PD-1+ T cells as predictive biomarker | Combination effects difficult to dissect; Limited long-term data; Patient heterogeneity in response | NCT02772679 | |
| Systemic Lupus Erythematosus | Active SLE | Low-dose IL-2 | Phase I/II | Increased Treg numbers; Reduced SLEDAI scores; Favorable safety profile; Restored Treg function | Optimal dose/duration unclear; Heterogeneous patient populations; Limited Phase III data | NCT02955615 |
| SLE | Novel IL-2 analogs (NKTR-358, efavaleukin alfa, MK-6194) | Phase I/II | Prolonged half-life; Enhanced Treg selectivity; Improved patient compliance | Early development stage; Long-term safety unknown; Cost considerations | NCT03556007 | |
| Multiple Sclerosis | MS (various forms) | Low-dose IL-2 | Phase II (RCT) | Modest delayed Treg expansion; Elevated Treg frequencies in some patients; No significant clinical benefit | Attenuated response vs. other autoimmune diseases; Clinical outcomes not significant; Patient selection unclear | NCT02424396 |
| Pemphigus & Autoimmune Skin Diseases | Pemphigus vulgaris | DSG3-specific Tregs | Phase I/IIa | Establishes feasibility of antigen-specific approach; Safe and well-tolerated | Early phase; Efficacy not yet demonstrated; Manufacturing complexity | NCT03239470 |
| Inflammatory Bowel Disease | Crohn's disease | Ovalbumin-specific Tregs (CATS29) | Phase I/IIa | Safety demonstrated; Potential clinical benefit; Compatible with gut inflammation | Model antigen (not disease-relevant); Limited efficacy data; Small sample size | NCT03185000 |
Typical clinical applications of regulatory T cell therapy in autoimmune diseases.
T1D, type 1 diabetes; Tregs, regulatory T cells; SLE, systemic lupus erythematosus; IL-2, interleukin-2; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; MS, multiple sclerosis; RCT, randomized controlled trial; DSG3, desmoglein 3; PD-1, programmed cell death protein 1.
Figure 2
2.2.1.1 T1D
In T1D, regarding Treg cell monotherapy, multiple phase 2 clinical trials have demonstrated that a single infusion of autologous polyclonally expanded Treg cells is safe in children and adolescents with recent-onset T1D, yet it failed to significantly delay β-cell functional decline (no significant difference in C-peptide level reduction) (39, 40). The limited efficacy of Treg therapies in preserving β-cell function in T1DM may reflect late intervention timing after substantial β-cell loss, and whether targeting earlier disease stages could improve outcomes warrants investigation. Additionally, the diabetogenic milieu may compromise Treg stability and function, suggesting that genetic engineering approaches to enhance FOXP3 stability or inflammatory resistance merit exploration. Furthermore, the lack of antigen specificity in polyclonal Treg products may limit therapeutic precision, raising the possibility that TCR-engineered or CAR-Treg strategies targeting islet autoantigens could offer improved efficacy, although clinical validation remains needed. Although ex vivo expanded Treg cells exhibit robust activity and suppressive capacity, their in vivo persistence and functionality remain limited, with expansion fold inversely correlating with therapeutic efficacy (39, 41). Regarding Treg-based combination immunotherapy, co-administration of Treg cells with anti-CD20 antibody (rituximab) significantly attenuated β-cell function loss in children with new-onset T1D, preserving C-peptide levels, reducing insulin requirements, and prolonging remission periods in a subset of patients (42, 43). PD-1-positive T cells may serve as a biomarker for predicting combination therapy efficacy (43). Furthermore, low-dose IL-2 selectively promotes in vivo Treg cell expansion, with high responders demonstrating superior C-peptide preservation and enhanced immunoregulatory function (44, 45). Additionally, dendritic cell-based therapies (such as AVT001) and anti-thymocyte globulin (ATG) can also delay T1D progression through modulation of the Treg/Teff balance (46–48).
2.2.1.2 SLE
Patients with SLE commonly exhibit reduced Treg cell numbers and functional impairment, resulting in disrupted immune tolerance and enhanced autoimmune responses (49). Treg deficiency is closely associated with dysregulation of the IL-2 signaling pathway, and the Treg/Th17 imbalance is considered one of the central mechanisms in SLE pathogenesis (49). Low-dose IL-2 can selectively expand Tregs, restore their immunosuppressive function, and ameliorate disease activity in SLE patients (49–51). Multiple randomized controlled trials and systematic reviews have demonstrated that low-dose IL-2 therapy significantly increases Treg numbers, reduces SLEDAI scores, and exhibits favorable safety profiles (52–54). Novel IL-2 analogs (such as NKTR-358, efavaleukin alfa, and MK-6194) further enhance therapeutic efficacy and patient compliance through prolonged half-life and enhanced Treg selectivity (55, 56).
Ex vivo-expanded autologous Treg cell infusion has shown promise in ameliorating SLE manifestations in animal models and selected clinical cases, with some patients demonstrating long-term Treg survival in vivo (57, 58). Emerging cellular therapies, including anti-CD19 CAR-Tregs and Sm antigen-specific Tregs, have exhibited robust efficacy and safety in animal and humanized mouse models, effectively suppressing autoreactive B cells and attenuating the progression of renal injury (57, 59). Additionally, various other therapeutic modalities—including pharmacological agents, exosomes, nanoparticles, and metabolic regulation—have demonstrated potential in modulating Treg/Th17 balance, promoting Treg differentiation, and improving immune dysregulation and clinical manifestations in SLE animal models and selected patient cohorts (60–62). However, although polyclonal Tregs have demonstrated therapeutic efficacy in SLE patients, their clinical translation remains limited due to several challenges, including the large number of cells required for infusion, lack of tissue-specific targeting, and inadequate in vivo persistence. Moreover, to date, no clinical trials of CAR-Treg therapy for SLE have been initiated. Key bottlenecks remain, including transduction efficiency, long-term stability, safety concerns, and the actual functionality of CAR-Tregs in complex inflammatory microenvironments. Further clinical application of CAR-Tregs is eagerly anticipated.
2.2.1.3 RA
Animal models and early-phase clinical studies have demonstrated that infusion of autologous or allogeneic Tregs can alleviate joint inflammation and restore immune tolerance (63, 64).
Multiple studies have confirmed that low-dose IL-2 selectively expands Tregs, improves the Treg/Th17 ratio in patients with RA, and alleviates disease activity with a favorable safety profile (65, 66). For example, Wang et al. demonstrated that refractory RA patients exhibited absolute CD4+ Treg depletion rather than Th17 expansion, and that low-dose IL-2 therapy (0.5 million IU, subcutaneously for 5 days) selectively restored Treg numbers, rebalanced Th17/Treg ratios, and induced clinical remission without adverse effects (65). Yan et al. demonstrated that difficult-to-treat (D2T) RA patients exhibited significant reductions in circulating T cells, CD4+ T cells, and particularly Tregs compared to healthy controls and treatment-responsive RA patients, resulting in elevated Th17/Treg ratios. In their study of 1, 042 RA patients and 339 healthy controls, low-dose IL-2 therapy (0.5 MIU daily, subcutaneously for 5 days) effectively expanded Treg populations across all RA groups without adverse effects, suggesting a unique lymphocyte depletionn phenotype in D2T RA amenable to IL-2 intervention (66). However, large-scale trials with long-term follow-up data remain limited.
2.2.1.4 MS
In randomized, double-blind, placebo-controlled trials involving patients with MS, IL-2 therapy elicited modest and delayed Treg expansion, with some patients demonstrating elevated Treg frequencies and enhanced activation phenotypes; however, the response was relatively attenuated compared to that observed in other autoimmune diseases, and clinical benefits did not reach statistical significance (67). Novel IL-2 variants, such as efavaleukin alfa and MK-6194, have demonstrated more robust Treg expansion and improved safety profiles in diseases including SLE, with certain candidates advancing into early-phase clinical investigations for MS-related indications (68, 69). Several approved MS therapeutics (including siponimod, cladribine, and dimethyl fumarate) can indirectly promote Treg expansion or functional enhancement. For instance, siponimod treatment in secondary progressive MS (SPMS) patients enriches Treg and regulatory B cell populations, facilitating immune tolerance (70); cladribine therapy increases Treg abundance in cerebrospinal fluid (CSF), suggesting modulation of the central nervous system immune microenvironment (71); dimethyl fumarate elevates Treg proportions and ameliorates inflammatory responses (72). Emerging strategies, such as combination therapy with low-dose IL-2 and Treg expansion, or co-administration of Tregs with mesenchymal stem cells, have demonstrated synergistic immunomodulatory and neuroprotective effects in preclinical animal models and early-phase clinical studies (73).
2.2.1.5 Pemphigus and other autoimmune skin diseases
Pemphigus vulgaris and related pemphigoid diseases are driven by autoantibodies against intercellular or basement membrane antigens, and Tregs are often numerically or functionally deficient in this setting (74, 75). Early-phase trials have explored the use of polyclonal autologous Tregs, and disease-relevant, antigen-specific Tregs in pemphigus to suppress autoreactive B and T cell responses (76). NCT03239470 has completed its early-phase evaluation, reporting favorable safety and tolerability; while efficacy signals require confirmation in larger cohorts, these efforts establish the feasibility of antigen-specific Treg approaches in autoimmune dermatology and support further development of DSG3-specific Tregs or broader autoreactive-Treg products as a means to attenuate pathogenic autoantibody production and inflammation. Mechanistically, DSG3-directed Tregs are anticipated to engage autoreactive B cells and Th1/Th17 effector pathways, rebalancing the humoral and cellular arms of the disease without general immunosuppression (77, 78).
In fact, Treg deficiency and Th17/Treg dysregulation represent pivotal pathogenic mechanisms across various autoimmune dermatoses, including vitiligo, alopecia areata, psoriasis, and systemic sclerosis (79–81). Therapeutic strategies aimed at restoring Treg homeostasis—via cellular expansion, functional potentiation, or enhanced cutaneous recruitment—hold promise for inducing antigen-specific tolerance and controlling skin inflammation (13, 81, 82). Despite this mechanistic rationale, most Treg-based interventions remain investigational, and rigorous clinical validation is required to address critical issues of efficacy persistence, infectious and neoplastic complications, and dermatologic specificity.
2.2.1.6 Inflammatory bowel disease
Inflammatory bowel disease (IBD) remains an area of active Treg investigation because mucosal tolerance is a central driver of disease activity. In Crohn’s disease, trials employing ovalbumin-specific Tregs (CATS29) demonstrated safety and potential clinical benefit, with completed phase I/IIa testing (NCT03185000) suggesting that antigen-directed Tregs can be delivered in a manner compatible with gut inflammation and may modulate mucosal immune responses (83, 84). Although these studies used model antigen constructs, they provide a critical proof-of-concept for the feasibility of tolerogenic Treg therapy in human intestinal inflammation. The next generation of trials is expected to employ Crohn’s disease–relevant antigen specificities or prospectively tailored allo- or autologous Tregs to enhance localization to inflamed gut tissue and to suppress pathogenic Th1/Th17–driven pathways.
2.2.1.7 Autoimmune hepatitis and other autoimmune liver diseases
Autoimmune hepatitis (AIH) represents a prototypic liver-directed autoimmune condition in which Treg-based strategies have been evaluated to reduce reliance on systemic immunosuppression (85). Autologous Treg infusion in AIH has been studied in early-phase trials (including I/IIa cohorts) with immunosuppressant tapering as a key outcome (85). These studies indicate that ex vivo expanded Tregs can be administered safely and may contribute to improved disease control, though data on long-term durability and histological endpoints remain limited. The AIH experience aligns with a broader concept of employing tolerogenic Tregs to recalibrate hepatic immune responses while preserving host defense.
2.2.1.8 Other autoimmune diseases with emerging treg approaches
Explorations in additional autoimmune conditions—such as autoimmune thyroiditis (Hashimoto’s thyroiditis and Graves’ disease), celiac disease, and certain autoimmune skin and mucosal disorders—have yielded encouraging signals that Treg-directed therapies can modulate organ-specific immunopathology. In thyroiditis and celiac disease, preclinical data support Treg induction and functional stabilization as a means to dampen tissue-specific autoreactivity and restore mucosal or organ tolerance (86). Early clinical efforts in these diseases emphasize safety and tolerability, with expanding interest in antigen-specific Tregs and low-dose IL-2–mediated Treg enrichment as enabling strategies for disease-modifying responses (87). While larger, disease-specific trials are still needed to define efficacy endpoints, the accumulated data across autoimmune diseases consistently point to several shared principles: restoration of Treg numbers and function, enhancement of Treg stability in inflammatory milieus, and preferential expansion of regulatory compared with effector T cell subsets.
2.2.2 Transplantation medicine
Tregs play a pivotal role in maintaining immune homeostasis and promoting tolerance in transplantation medicine (88). These cells suppress alloreactive immune responses, thereby reducing the risk of graft rejection and potentially minimizing the need for long-term immunosuppression (89, 90). Preclinical studies have demonstrated their efficacy in controlling acute and chronic rejection, highlighting their therapeutic potential for inducing operational tolerance in transplant recipients (91).
Clinical translation of Treg-based therapies in transplantation medicine has progressed significantly, with several Phase I and II trials investigating their safety and efficacy. Polyclonal Tregs, expanded ex vivo from recipient or donor sources, have been administered in settings such as solid organ transplantation and hematopoietic stem cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) (91, 92). For instance, early-phase trials have utilized ex vivo-expanded CD4+CD25+Foxp3+ Tregs, showing promising results in reducing immunosuppressive drug requirements and improving graft survival (89, 91).
Ongoing clinical efforts also focus on optimizing Treg manufacturing and delivery. For example, trials have investigated the use of donor-derived Tregs in liver and kidney transplantation, with preliminary evidence suggesting improved tolerance induction and reduced rejection episodes (90, 93). Future directions include leveraging metabolic programming to enhance Treg functionality in vivo, as well as combining Treg therapy with tolerogenic protocols such as costimulation blockade. While clinical outcomes are still evolving, Treg-based interventions represent a transformative approach toward achieving durable transplantation tolerance.
2.2.3 Other frontiers in treg therapy
Beyond the well-established domains of autoimmunity and transplantation, Treg–based approaches are being explored in a broader range of non-malignant conditions, reflecting a growing appreciation for their roles in tissue homeostasis, repair, and systemic metabolism. In allergic diseases and airway inflammation, Tregs restrain allergen-driven Th2 responses and eosinophilic inflammation through cytokines such as IL-10 and TGF-β, contributing to mucosal tolerance and reduced airway hyperreactivity (94). Preclinical models of asthma and allergic rhinitis show that augmentation or adoptive transfer of Tregs can dampen local inflammation, while early human studies leveraging low-dose IL-2 to expand or stabilize Tregs indicate safety and potential biomarker improvements, underscoring the feasibility of organ-specific regulatory strategies; nonetheless, achieving efficient trafficking to the airway mucosa and preserving Treg stability in a Th2-biased environment remain critical challenges (95, 96).
In tissue repair and regenerative immunity, Tregs contribute to healing processes through mediators such as amphiregulin and interactions with resident stem or progenitor cells, with preclinical evidence showing accelerated wound repair and reduced fibrotic remodeling in various organ systems; translating these findings requires precise control of timing and localization to maximize repair while preserving antimicrobial defenses, with delivery modalities ranging from local injections to biomaterial-assisted recruitment and tissue-homing engineering (97, 98).
In immunometabolic diseases, Tregs modulate inflammatory tone and insulin sensitivity within adipose tissue, offering a mechanistic basis for treating metabolic syndrome and obesity-related inflammation; while animal models document improved metabolic outcomes upon Treg enhancement, human data remain preliminary, and strategies to selectively enrich Tregs in metabolic depots without inducing systemic immunosuppression are actively being explored (99).
The neuroinflammatory and CNS injury frontier draws on evidence that Tregs can modulate microglial activation and downstream inflammatory cascades, potentially limiting secondary injury and aiding recovery after stroke, traumatic brain injury, or spinal cord injury; however, crossing the blood–brain barrier, sustaining regulatory function in the CNS milieu, and balancing neuroprotection with adequate host defense are central obstacles that guide the design of delivery strategies and patient selection in early clinical work (100, 101).
In dermatology and mucosal health beyond autoimmune skin diseases, the skin and mucosal surfaces house specialized Treg populations that regulate barrier integrity and local immunity; preclinical studies suggest that enhancing regulatory networks can attenuate barrier-related inflammation and promote healing, with early clinical signals in related inflammatory conditions indicating tolerability and potential benefit, pointing to the value of local delivery and integration with barrier-restoration therapies to optimize outcomes (102).
Finally, other organ-system considerations and rare diseases comprise an expanding arena in which chronic inflammation, fibrosis, or remodeling may be modulated by Tregs; preclinical findings across liver, lung, and heart contexts hint at potential benefit, while early clinical exploration remains cautious and hypothesis-generating, underscoring the need for disease-specific endpoints, robust biomarkers, and long-term safety surveillance (14, 103).
Taken together, these frontier areas reflect a broadening recognition that Tregs can support therapeutic objectives beyond classical autoimmunity and transplantation, but progress will depend on rigorous, multidisciplinary studies that define optimal cell products, dosing regimens, routes of administration, and combinatorial strategies that maximize tissue-specific benefits while preserving systemic immune competence.
2.3 Future treatment directions
Future advances in Treg therapy for non-malignant diseases should build on mechanistic insight and translational progress to deliver disease-focused products that are safe, scalable, and monitorable in real-world clinical settings. The overarching goal is to translate fundamental Treg biology into precise, tissue-tolerant interventions whose effects can be rigorously evaluated in well-designed trials across autoimmune diseases and transplantation contexts. This trajectory will require harmonizing cell engineering, tissue targeting, dosing regimens, manufacturing pipelines, and immunomonitoring.
2.3.1 Engineering tregs for precision tolerance
A central pillar of precision Treg therapy is the generation of antigen-specific regulatory cells, such as CAR-Tregs and TCR-Tregs, which can direct immunosuppressive activity to disease-relevant antigens while reducing systemic immunosuppression (104). Achieving a favorable safety profile necessitates careful balancing of potent local tolerance with preservation of host defense and avoidance of off-target effects. Enhancing the stability and suppressive phenotype of Tregs in inflammatory environments is critical; strategies that promote FOXP3 stability and durable epigenetic imprinting, including maintenance of TSDR demethylation and modulation of metabolic programs, are actively explored to sustain regulatory function (32, 105). Manufacturing practicality also guides design choices: non-viral engineering approaches, including mRNA-based methods and transposon systems, offer potential reductions in manufacturing complexity and regulatory burden, provided that efficacy and genomic safety are thoroughly validated (106, 107). Beyond genetic modification, advances in bioengineering, such as synthetic biology constructs that provide tunable co-stimulation or conditional regulatory circuits, hold promise for boosting potency while minimizing risk. Equally important is embedding tissue-homing features within engineered Tregs to promote localized immunoregulation at sites of inflammation or injury.
2.3.2 Targeting tissue localization and delivery
Effective tissue targeting requires aligning Treg migratory capacity with the organ or tissue involved in disease. Engineering expression of disease-relevant chemokine receptors and adhesion molecules can enhance selective trafficking to affected sites, thereby improving efficacy and reducing systemic immunosuppression (108). Local administration strategies, including intralesional or organ-specific injections and the use of biomaterial platforms such as scaffolds or hydrogel systems, may concentrate Tregs at pathological sites, potentially increasing persistence and function (109). Comprehensive in vivo tracking, through imaging modalities or safe labeling approaches, supports safety and dosing decisions by delineating biodistribution and persistence over time. Taken together, optimized localization strategies should be designed to maximize regulatory impact where it is most needed while maintaining overall immune competence.
2.3.3 Regimen design and combination strategies
The clinical implementation of Treg therapy depends critically on cell source selection and manufacturing processes. Polyclonal Tregs are most commonly derived from autologous peripheral blood mononuclear cells (PBMCs), though allogeneic sources—including umbilical cord blood and third-party donors—offer potential “off-the-shelf” advantages, albeit with considerations regarding HLA matching and persistence (110). Enrichment strategies typically rely on fluorescence-activated cell sorting (FACS) or magnetic bead-based isolation targeting CD4+CD25+CD127low cells, with some protocols incorporating additional markers such as CD45RA to select naïve Treg subsets with superior stability (111). Ex vivo expansion is generally achieved through anti-CD3/CD28 bead stimulation supplemented with high-dose IL-2, with or without rapamycin to enhance FOXP3 stability and suppress effector T cell outgrowth (112). These manufacturing variables—including expansion duration, feeder cell use, and culture conditions—substantially influence product purity, FOXP3 demethylation status, suppressive potency, and phenotypic stability, contributing to heterogeneity across clinical studies and complicating cross-trial comparisons (113).
Beyond manufacturing considerations, Treg therapy will likely be most effective when integrated into tolerogenic regimens that sustain regulatory activity without unduly compromising host defense (114). Co-administration with low-dose IL-2 or other tolerogenic signals can support the expansion and maintenance of regulatory populations, yet requires careful timing and dose optimization to preserve effector responses necessary for pathogen control and anti-tumor surveillance (115, 116). Combination strategies that pair Tregs with other immunomodulatory modalities—such as B cell–targeted therapies, tolerogenic dendritic cells, or mesenchymal stromal cells—may yield synergistic benefits by simultaneously tempering multiple arms of the immune response (117, 118). Regimens should be disease-specific, reflecting underlying biology such as organ involvement, autoantigen repertoires, and inflammatory milieu, and should incorporate adaptive monitoring to adjust cell dosing and supportive therapies. Biomarker-guided personalization, leveraging flow cytometry, single-cell analyses, and functional assays, can inform patient selection, product choice (polyclonal versus antigen-specific), manufacturing protocol optimization, and treatment cadence, facilitating a move toward precision medicine in Treg-based interventions.
3 Challenges and research priorities
A major challenge in translating Treg therapies lies in the intrinsic heterogeneity and contextual stability of Treg subsets across tissues and diseases. Understanding how to preserve and direct regulatory phenotypes within diverse inflammatory milieus is essential, and will benefit from multi-omics and single-cell approaches to guide product design and patient selection. Crucially, the potent immunosuppressive capacity that makes Tregs therapeutically attractive also raises significant safety concerns. Pan-immunosuppression may impair host defense against pathogens, potentially leading to reactivation of latent infections such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), or tuberculosis, and may theoretically compromise tumor immunosurveillance. Additionally, Treg plasticity poses a distinct risk: under certain inflammatory conditions, particularly those rich in IL-6 and IL-1β, Tregs may lose FOXP3 expression and convert into pathogenic effector phenotypes, including Th17-like or Th1-like cells, paradoxically exacerbating tissue inflammation rather than suppressing it. These phenotypic shifts have been documented in preclinical models and warrant careful monitoring in clinical settings. Translational barriers, including manufacturing scale-up, cost, regulatory scrutiny, and the need for comprehensive long-term safety data, must be addressed through investment in GMP-grade workflows, non-viral engineering platforms, and standardized potency and identity assays. While randomized controlled trials remain the gold standard for establishing efficacy, several autoimmune and transplantation studies have reported encouraging safety signals and clinical improvements in single-arm designs; these findings, albeit limited, provide important feasibility data and help shape the design of future multicenter, controlled studies. The field would benefit from biomarker development to enable pharmacodynamic and pharmacokinetic assessment, including Treg frequency and functionality, FOXP3/TSDR status, cytokine signatures, and tissue infiltration patterns, as well as predictive markers for response and adverse events. Finally, a proactive safety framework that anticipates risks of generalized immunosuppression, latent pathogen reactivation, or unintended pro-inflammatory shifts due to Treg instability should be integrated into product development from the outset.
4 Conclusion
Regulatory T cell therapy holds tangible promise for non-malignant diseases by restoring immune tolerance while preserving host defense. Realizing this potential will require disease-focused Treg products that combine antigen specificity with targeted tissue delivery, underpinned by rigorous manufacturing standards, comprehensive safety oversight, and dynamic immunomonitoring. Engineered Tregs, including CAR-Tregs and TCR-Tregs, together with rational combination regimens and tolerogenic backbones, are likely to define the near-term clinical trajectory. Progress will depend on well-designed multicenter trials, standardized endpoints, and robust biomarkers that enable patient stratification and adaptive therapy. Through iterative advances in cell engineering, delivery strategies, and translational science, Treg-based therapy can mature from an experimental modality into a mainstream clinical option that improves outcomes across autoimmune diseases and transplantation.
Statements
Author contributions
SD: Writing – original draft, Conceptualization, Data curation. JZ: Writing – original draft, Methodology, Data curation. ZC: Data curation, Writing – review & editing, Project administration. YH: Supervision, Writing – review & editing, Project administration. YZ: Conceptualization, Funding acquisition, Writing – review & editing. HG: Funding acquisition, Writing – review & editing, Conceptualization, Project administration.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the National Natural Science Foundation of China (82400649) and Science and Health Joint Medical Research Program of Chongqing Municipality (2024ZDXM009, 2026QNXM018).
Conflict of interest
The author(s) 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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Summary
Keywords
regulatory T cells, autoimmune diseases, immune-mediated diseases, adoptive cell therapy, CAR-Treg
Citation
Duan S, Zhang J, Chen Z, He Y, Zhang Y and Guo H (2026) Regulatory T cell therapy in autoimmune and immune-mediated diseases: from basic research to clinical practice and future perspectives. Front. Immunol. 17:1772001. doi: 10.3389/fimmu.2026.1772001
Received
20 December 2025
Revised
24 February 2026
Accepted
17 April 2026
Published
07 May 2026
Volume
17 - 2026
Edited by
Karina Pino-Lagos, University of the Andes, Chile
Reviewed by
Jaxaira Maggi, Spanish National Research Council (CSIC), Spain
Fangzhou Li, Chinese Academy of Sciences (CAS), China
Updates
Copyright
© 2026 Duan, Zhang, Chen, He, Zhang and Guo.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Hong Guo, hguo_cgh2021@cqu.edu.cn; Yingzhi Zhang, zhang_yingzhi@cqu.edu.cn
†These authors have contributed equally to this work
Disclaimer
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