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Regulatory T cell
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Regulatory T cell
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The regulatory T cells (Tregs /ˈtiːrɛɡ/ or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells.[1] Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells.[2] Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.[3]

Mouse models have suggested that modulation of Treg cells can treat autoimmune disease and cancer and can facilitate organ transplantation[4] and wound healing.[5] Their implications for cancer are complicated. Treg cells tend to be upregulated in individuals with cancer, and they seem to be recruited to the site of many tumors. Studies in both humans and animal models have implicated that high numbers of Treg cells in the tumor microenvironment is indicative of a poor prognosis, and Treg cells are thought to suppress tumor immunity, thus hindering the body's innate ability to control the growth of cancerous cells.[6] Immunotherapy research is studying how regulation of T cells could possibly be utilized in the treatment of cancer.[7]

Populations

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T regulatory cells are a component of the immune system that suppress immune responses of other cells. This is an important "self-check" built into the immune system to prevent excessive reactions. Regulatory T cells come in many forms with the most well-understood being those that express CD4, CD25, and FOXP3 (CD4+CD25+ regulatory T cells). These Treg cells are different from helper T cells.[8] Another regulatory T cell subset is Treg17 cells.[9] Regulatory T cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity.[10]

CD4+ FOXP3+ CD25(high) regulatory T cells have been called "naturally occurring" regulatory T cells[11] to distinguish them from "suppressor" T cell populations that are generated in vitro. Additional regulatory T cell populations include Tr1, Th3, CD8+CD28−, and Qa-1 restricted T cells. The contribution of these populations to self-tolerance and immune homeostasis is less well defined. FOXP3 can be used as a good marker for mouse CD4+CD25+ T cells, although recent studies have also shown evidence for FOXP3 expression in CD4+CD25− T cells. In humans, FOXP3 is also expressed by recently activated conventional T cells and thus does not specifically identify human Tregs.[12]

Development

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All T cells derive from progenitor cells in the bone marrow, which become committed to their lineage in the thymus. All T cells begin as CD4-CD8-TCR- cells at the DN (double-negative) stage, where an individual cell will rearrange its T cell receptor genes to form a unique, functional molecule, which they, in turn, test against cells in the thymic cortex for a minimal level of interaction with self-MHC. If they receive these signals, they proliferate and express both CD4 and CD8, becoming double-positive cells. The selection of Tregs occurs on radio-resistant hematopoietically derived MHC class II-expressing cells in the medulla or Hassall's corpuscles in the thymus. At the DP (double-positive) stage, they are selected by their interaction with the cells within the thymus, begin the transcription of Foxp3, and become Treg cells, although they may not begin to express Foxp3 until the single-positive stage, at which point they are functional Tregs. Tregs do not have the limited TCR expression of NKT or γδ T cells; Tregs have a larger TCR diversity than effector T cells, biased towards self-peptides.

The process of Treg selection is determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a Treg is a "Goldilocks" process - i.e. not too high, not too low, but just right;[13] a T cell that receives very strong signals will undergo apoptotic death; a cell that receives a weak signal will survive and be selected to become an effector cell. If a T cell receives an intermediate signal, then it will become a regulatory cell. Due to the stochastic nature of the process of T cell activation, all T cell populations with a given TCR will end up with a mixture of Teff and Treg – the relative proportions determined by the affinities of the T cell for the self-peptide-MHC. Even in mouse models with TCR-transgenic cells selected on specific-antigen-secreting stroma, deletion or conversion is not complete.

After interaction with the self-peptide MHC complex, a T cell must upregulate IL-2R, CD25 and the TNFR superfamily members GITR, OX40 and TNFR2 to become a CD25+FOXP3− Treg cell progenitor. Expression of the transcription factor FOXP3 is then required for this cell to become a mature Treg. Foxp3 expression is driven by γ-chain (CD132) dependent cytokines, in particular IL-2 and/or IL-15.[14][15] IL-2 alone is not sufficient to stimulate Foxp3 expression. While IL-2 is produced by self-reactive thymocytes, IL-15 is produced by stromal cells of the thymus, mainly mTECs and cTECs.[14]

Recently, another subset of Treg precursors was identified. This subset lacks CD25 and has low expression of Foxp3. Its development is mainly dependent on IL-15. This subset has a lower affinity for self antigens than the CD25+Foxp3high subset. Both subsets generate mature Treg cells after stimulation with IL-2 with comparable efficiency both in vitro and in vivo. CD25+Foxp3high progenitors exhibit increased apoptosis and develop into mature Treg cells with faster kinetics than Foxp3low progenitors.[16] Tregs derived from CD25+Foxp3high progenitors protect from experimental auto-immune encephalomyelitis, whereas those derived from CD25+Foxp3low progenitors protect from T-cell induced colitis.[14]

Mature CD25+Foxp3+ Tregs can be also divided into two different subsets based on the expression level of CD25, GITR, and PD-1. Tregs expressing low amounts of CD25, GITR and PD-1 limit the development of colitis by promoting the conversion of conventional CD4+ T cells into pTreg. Tregs highly expressing CD25, GITR and PD-1 are more self-reactive and control lymphoproliferation in peripheral lymph nodes - they may have the ability to protect against autoimmune disorders.[14]

Foxp3+ Treg generation in the thymus is delayed by several days compared to Teff cells and does not reach adult levels in either the thymus or periphery until around three weeks post-partum. Treg cells require CD28 co-stimulation and B7.2 expression is largely restricted to the medulla, the development of which seems to parallel the development of Foxp3+ cells. It has been suggested that the two are linked, but no definitive link between the processes has yet been shown. TGF-β is not required for Treg functionality, in the thymus, as thymic Tregs from TGF-β insensitive TGFβRII-DN mice are functional.

Thymic recirculation

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It has been observed that some FOXP3+ Treg cells recirculate to thymus. These Tregs were mainly present in thymic medulla, which is the main site of Treg cells differentiation.[17] The presence of these cells in the thymus or their addition to fetal thymic tissue culture suppress the development of new Treg cells by 34–60%[17] without affecting conventional T cells. This suggests that these Tregs only inhibit de novo development of Treg cells. The molecular mechanism of this process depends upon the ability of Tregs to adsorb IL-2 from their microenvironments, an ability that allows them to induce the apoptosis of T cells that need IL-2 as main growth factor.[18] Recirculating Tregs in the thymus express high levels of the high-affinity IL-2 receptor α chain (CD25), encoded by the Il2ra gene, which gathers IL-2 from thymic medulla and decreases its concentration. In contrast, newly-generated FOXP3+ Treg cells in thymus do not have a high level of Il2ra expression.[17] IL-2 is a cytokine necessary for the development of Treg cells in the thymus. It is involved in the proliferation and survival of all T cells, but IL-15 may replace its activity in many contexts. However, Treg cells' development is dependent on IL-2.[19] A population of CD31 negative Treg cells has been found in the human thymus,[17] suggesting that CD31 may be used as a marker for newly-generated Treg cells and other T lymphocytes. Mature and peripheral Treg cells downregulate the expression of CD31,[20] suggesting that this mechanism of thymic Treg development may also be functional in humans.

There is probably also positive regulation of thymic Treg cells development caused by recirculating Treg cells into thymus. A thymic population of CD24 low FOXP3+ has been discovered with increased expression of IL-1R2 (Il1r2) compared to peripheral Treg cells.[21][22] High concentrations of IL-1β caused by inflammation decrease de novo development of Treg cells in the thymus.[22] The presence of recirculating Treg cells in the thymus with high IL1R2 expression during inflammatory conditions helps to uptake IL-1β and reduce its concentration in the medulla microenvironment, thus aiding the development of de novo Treg cells.[22] Binding of IL-1β to IL1R2 on the surface of Treg cells does not cause signal transduction because the Intracellular (TIR) Toll interleukin-1 receptor domain, which is normally present in innate immune cells, is absent in Tregs.[23]

Function

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The immune system must be able to discriminate between self and non-self. When self/non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells (IPEX syndrome – see also below).

Diagram of regulatory T cell, effector T cells and dendritic cell showing putative mechanisms of suppression by regulatory T cells.

The molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized and is the subject of intense research. In vitro experiments have given mixed results regarding the requirement of cell-to-cell contact with the cell being suppressed. The following represent some of the proposed mechanisms of immune suppression:

  • Regulatory T cells produce a number of inhibitory cytokines. These include TGF-β,[24] Interleukin 35,[25] and Interleukin 10.[26] It also appears that regulatory T cells can induce other cell types to express interleukin-10.[27]
  • Regulatory T cells can produce Granzyme B, which in turn can induce apoptosis of effector cells. Regulatory T cells from Granzyme B deficient mice are reported to be less effective suppressors of the activation of effector T cells.[28]
  • Reverse signalling through direct interaction with dendritic cells and the induction of immunosuppressive indoleamine 2,3-dioxygenase.[29]
  • Signalling through the ectoenzymes CD39 and CD73 with the production of immunosuppressive adenosine.[30][31]
  • Through direct interactions with dendritic cells by LAG3 and by TIGIT.[32][33] This review of Treg interactions with dendritic cells provides distinction between mechanisms described for human cells versus mouse cells.[34]
  • Another control mechanism is through the IL-2 feedback loop. Antigen-activated T cells produce IL-2 which then acts on IL-2 receptors on regulatory T cells alerting them to the fact that high T cell activity is occurring in the region, and they mount a suppressory response against them. This is a negative feedback loop to ensure that overreaction is not occurring. If an actual infection is present other inflammatory factors downregulate the suppression. Disruption of the loop leads to hyperreactivity, regulation can modify the strength of the immune response.[35] A related suggestion with regard to interleukin 2 is that activated regulatory T cells take up interleukin 2 so avidly that they deprive effector T cells of sufficient to avoid apoptosis.[18]
  • A major mechanism of suppression by regulatory T cells is through the prevention of co-stimulation through CD28 on effector T cells by the action of the molecule CTLA-4.[36]
  • Regulatory T cells also perform tissue-specific roles in repair, tolerance, and modulation of inflammation across the central nervous system, gastrointestinal tract, joints, skin, and lungs.[37]

Natural and induced regulatory T cells

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T regulatory lymphocytes develop during ontogeny either in the thymus or in the periphery. Accordingly, they are divided into natural and induced T regulatory cells.[38]

Natural T regulatory lymphocytes (tTregs, nTregs) are characterized by continuous expression of FoxP3 and T cell receptor (TCR) with relatively high autoaffinity. These cells are predominantly found in the body in the bloodstream or lymph nodes and serve mainly to confer tolerance to autoantigens.[38]

Induced (peripheral) T regulatory cells (iTregs, pTregs) arise under certain situations in the presence of IL-2 and TGF-b in the periphery and begin to express FoxP3 inducibly, thus becoming the functional equivalent of tTreg cells. iTregs, however, are found primarily in peripheral barrier tissues, where they are primarily involved in preventing inflammation in the presence of external antigens.[38]

The main features that differentiate tTreg and iTreg cells include Helios and Neuropilin-1, the presence of which suggests origin in the thymus. Another feature distinguishing these two Treg cell populations is the stability of FoxP3 expression in different settings.[38]

Induced T regulatory cells

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Induced regulatory T (iTreg) cells (CD4+ CD25+ FOXP3+) are suppressive cells involved in tolerance. iTreg cells have been shown to suppress T cell proliferation and experimental autoimmune diseases. These cells include Treg17 cells. iTreg cells develop from mature CD4+ conventional T cells outside of the thymus: a defining distinction between natural regulatory T (nTreg) cells and iTreg cells. Though iTreg and nTreg cells share a similar function iTreg cells have recently been shown to be "an essential non-redundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses".[39] Acute depletion of the iTreg cell pool in mouse models has resulted in inflammation and weight loss. The contribution of nTreg cells versus iTreg cells in maintaining tolerance is unknown, but both are important. Epigenetic differences have been observed between nTreg and iTreg cells, with the former having more stable FOXP3 expression and wider demethylation.

The small intestinal environment is high in vitamin A and is a location where retinoic acid is produced.[40] The retinoic acid and TGF-beta produced by dendritic cells within this area signal for production of regulatory T cells.[40] Vitamin A and TGF-beta promote T cell differentiation into regulatory T cells opposed to Th17 cells, even in the presence of IL-6.[41][42] The intestinal environment can lead to induced regulatory T cells with TGF-beta and retinoic acid,[43] some of which express the lectin-like receptor CD161 and are specialized to maintain barrier integrity by accelerating wound healing.[44] The Tregs within the gut are differentiated from naïve T cells after antigen is introduced.[45] It has recently been shown that human regulatory T cells can be induced from both naive and pre-committed Th1 cells and Th17 cells[46] using a parasite-derived TGF-β mimic, secreted by Heligmosomoides polygyrus and termed Hp-TGM (H. polygyrus TGF-β mimic).[47][48] Hp-TGM can induce murine FOXP3 expressing regulatory T cells that were stable in the presence of inflammation in vivo.[49] Hp-TGM-induced human FOXP3+ regulatory T cells were stable in the presence of inflammation and had increased levels of CD25, CTLA4 and decreased methylation in the FOXP3 Treg-Specific demethylated region compared to TGF-β-induced Tregs.[46]

RORγt+ regulatory T lymphocytes

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Approximately 30%–40% of colonic FoxP3+ Treg cells express the transcription factor RORγt.[50] The iTregs are able to differentiate into RORγt-expressing cells and thus acquire the phenotype of Th17 cells. These cells are associated with the functions of mucosal lymphoid tissues such as the intestinal barrier. In the intestinal lamina propria, 20-30% of Foxp3+ T regulatory cells expressing RORyt are found and this high proportion is strongly dependent on the presence of a complex gut microbiome. In germ-free (GF) mice, the population of RORγt+ T regulatory cells is strongly reduced, whereas recolonization by the specific pathogen-free (SPF) microbiota restores normal numbers of these lymphocytes in the gut. The mechanism by which the gut microbiota induces the formation of RORγt+ Treg cells involves the production of short-chain fatty acids (SCFAs), on which this induction is dependent. SCFAs are a by-product of fermentation and digestion of dietary fiber, therefore, microbial-free mice have very low concentrations of both SCFAs and RORγt Treg cells. Induction of RORγt Treg cells is also dependent on the presence of dendritic cells in adults, Thetis cells in neonatal and antigen presentation by MHC II.[51][52]

RORγt+ Treg cells are not present in the thymus and do not express Helios or Neuropilin-1, but have high expression of CD44, IL-10, ICOS, CTLA-4, and the nucleotidases CD39 and CD73, suggesting a strong regulatory function.[51]

Function of RORγt+ regulatory T lymphocytes

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Induction of RORγt+ Treg cells in lymph nodes of the small intestine is crucial for the establishment of intestinal luminal antigen tolerance. These cells are particularly important in the prevention of food allergies. One mechanism is the production of suppressive molecules such as the cytokine IL-10. These cells also suppress the Th17 cell population and inhibit the production of IL-17, thus suppressing the pro-inflammatory response.[51]

In mice, colonic RORγt+ Tregs are absent during the first two weeks after birth. Generation of RORγt+ Treg early after birth is essential to prevent the development of various intestinal immunopathologies later in life. Particularly crucial is a time period of gradual transition from relying solely on maternal milk to incorporating solid food, between 15 and 20 days of age, when a large number of microbial antigens is introduced and commensal microbiota are settling in the intestine. During this time, protective RORγt+ Treg cells are induced by the microbial antigens and normal intestinal homeostasis is sustained by induction of tolerance to commensal microbiota. Lack of RORγt+ Treg cell induction led in mice to the development of severe colitis.[53] The quantity of early-life-induced RORγt+ Tregs is influenced by maternal milk, particularly by the amount of IgA antibodies present in the maternal milk. In adult mice, RORγt+ Tregs and IgA exhibit mutual inhibition. Similarly, mice nursed by foster mothers with higher IgA titers in their milk will develop fewer RORγt+ Tregs compared to those fed with milk containing lower IgA titers.[54]

RORγt+ Tregs were also shown for their importance in oral tolerance and prevention of food allergies. Infants with developed food allergies have different composition of fecal microbiota in comparison to healthy infants and have increased IgE bound to fecal microbiota and decreased secretory IgA. In mice, protection against food allergies was induced by introduction of Clostridiales and Bacteroidales species. Upon their introduction, expansion of gut RORγt+ Treg cells in favor of GATA3+ Treg occurs,  mediating the protection against allergies.[55]

Deficiency of tryptophan, an essential amino acid, alters commensal microbiota metabolism which results in expansion of RORγt+ Treg cells and reduction of Gata3+ Treg cells. This induction is possibly regulated by stimulation of Aryl hydrocarbon receptor by metabolites produced by commensal bacteria using tryptophan as an energy source.[56]

Lower number of RORγt+ Treg cells is present in germ free mice colonized with microbiota associated with Inflammatory bowel disease compared to germ free mice colonized with healthy microbiota. Dysregulation of RORγt+ Treg cells favors the expansion of Th2 cells and lower number of RORγt+ Treg cells is compensated by increased Helios+ Treg cells. How exactly may RORγt+ Tregs protect from colitis is not yet known.[57]

RORγt+ regulatory T lymphocytes in cancer

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Pathological may be involvement of RORγt+ regulatory T cells in colorectal cancer. It was found, that RORγt+ Tregs which are able to express IL-17 are expanded in colorectal cancer and as cancer develops, they lose the ability to express anti-inflammatory IL-10. Similarly such RORγt+ Tregs expressing IL-17 are expanded in mucosa of patients with Crohn´s disease.[58][59] Depletion of RORγt+ Tregs in mice with colorectal cancer caused enhancement of reactivity of tumor-specific T cells and improved cancer immune surveillance. This improvement is not caused by the loss of IL-17 as that was proved to promote cancer progression.[59] In tumors of mice with conditional knockout of RORγt+ Tregs was confirmed downregulation of IL-6, reduction of IL-6 expressing CD11c+ dendritic cells and overexpression of CTLA-4. IL-6 mediates activation of STAT3 transcription factor which is critical for proliferation of cancer cells.[60]

Gata3+ regulatory T lymphocytes

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Another important subset of Treg cells are Gata3+ Treg cells, which respond to IL-33 in the gut and influence the regulation of effector T cells during inflammation. Unlike RORγt+ Treg cells, these cells express Helios and are not dependent on the microbiome.[52][61]

Gata3+ T regs are major immunosuppressors during intestinal inflammation and T regs use Gata3 to limit tissue inflammation. This cell population also restrict Th17 T cells immunity in the intestine, because Gata3-deficient T regs express higher Rorc and IL-17a transcript.[62]

Disease

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An important question is how the immunosuppressive activity of regulatory T cells is modulated during the course of an ongoing immune response. While the immunosuppressive function of regulatory T cells prevents the development of autoimmune disease, it is not desirable during immune responses to infectious microorganisms.

Infections

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Upon encounter with infectious microorganisms, the activity of regulatory T cells may be downregulated, either directly or indirectly, by other cells to facilitate elimination of the infection. Experimental evidence from mouse models suggests that some pathogens may have evolved to manipulate regulatory T cells to immunosuppress the host and so potentiate their own survival. For example, regulatory T cell activity has been reported to increase in several infectious contexts, such as retroviral infections (the most well-known of which is HIV), mycobacterial infections (e.g., tuberculosis[63]), and various parasitic infections including Leishmania and malaria.

Treg cells play major roles during HIV infection. They suppress the immune system, thus limiting target cells and reducing inflammation, but this simultaneously disrupts the clearance of virus by the cell-mediated immune response and enhances the reservoir by pushing CD4+ T cells to a resting state, including infected cells. Additionally, Treg cells can be infected by HIV, increasing the size of the HIV reservoir directly. Thus, Treg cells are being investigated as targets for HIV cure research.[64] Some Treg cell depletion strategies have been tested in SIV infected nonhuman primates, and shown to cause viral reactivation and enhanced SIV specific CD8+ T cell responses.[65]

Regulatory T cells have a large role in the pathology of visceral leishmaniasis and in preventing excess inflammation in patients cured of visceral leishmaniasis.

ALS

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There is some evidence that Treg cells may be dysfunctional and driving neuroinflammation in amyotrophic lateral sclerosis due to lower expression of FOXP3.[66] Ex vivo expansion of Treg cells for subsequent autologous transplant is currently being investigated after promising results were obtained in a phase I clinical trial.[67]

Pregnancy

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While regulatory T cells increase via polyclonal expansion both systemically and locally during healthy pregnancies to protect the fetus from the maternal immune response (a process called maternal immune tolerance), evidence suggests that this polyclonal expansion is impaired in preeclamptic mothers and their offspring.[68] Research suggests reduced production and development of regulatory T cells during preeclampsia may degrade maternal immune tolerance, leading to the hyperactive immune response characteristic of preeclampsia.[69]

Cancer

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The recruitment and maintenance of Treg cells in the tumor microenvironment

CD4+ regulatory T cells are often associated with solid tumours in both humans and murine models. Increased numbers of regulatory T cells in breast, colorectal and ovarian cancers is associated with a poorer prognosis.[70]

CD70+ non-Hodgkin lymphoma B cells induce FOXP3 expression and regulatory function in intratumoral CD4+CD25− T cells.[71]

Most tumors elicit an immune response in the host that is mediated by tumor antigens, thus distinguishing the tumor from other non-cancerous cells. This causes large numbers of tumor-infiltrating lymphocytes (TILs) to appear in the TME.[72] These lymphocytes may target cancerous cells and therefore slow or terminate tumor development. However, this process is complicated because Treg cells seem to be preferentially trafficked to the TME. While Treg cells normally make up only about 4% of CD4+ T cells, they can make up as much as 20–30% of the CD4+ population around the TME.[73]

The ratio of Treg to effector T cells in the TME is a determining factor in the success of the cancer immune response. High levels of Treg cells in the TME are associated with poor prognosis in many cancers,[74] such as ovarian, breast, renal, and pancreatic cancer.[73] This indicates that Treg cells suppress effector T cells and hinder the body's immune response against the cancer. However, in some types of cancer the opposite is true, and high levels of Treg cells are associated with a positive prognosis. This trend is seen in cancers such as colorectal carcinoma and follicular lymphoma. This could be due to Treg cells' ability to suppress general inflammation, which is known to trigger cell proliferation and metastasis .[73] These opposite effects indicate that Tr cells' role in the development of cancer is highly dependent on both type and location of the tumor.

Although it is still not entirely understood how Treg cells are preferentially trafficked to the TME, the chemotaxis is probably driven by the production of chemokines by the tumor. Treg infiltration into the TMEis facilitated by the binding of the chemokine receptor CCR4, which is expressed on Treg cells, to its ligand CCL22, which is secreted by many types of tumor cells.[75] Treg cell expansion at the site of the tumor could also explain the increased levels of Treg cells. The cytokine, TGF-β, which is commonly produced by tumor cells, is known to induce the differentiation and expansion of Treg cells.[75]

Forkhead box protein 3 (FOXP3) as a transcription factor is an essential molecular marker of Treg cells. FOXP3 polymorphism (rs3761548) might be involved in the gastric cancer progression through influencing Treg function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β.[76]

Treg cells present in the TME  can be either induced Tregs or natural (thymic) Tregs which develop from naive precursors. However, tumor-associated Tregs may also originate from IL-17A+Foxp3+ Tregs which develop from Th17 cells.[77][78]

In general, the immunosuppression of the TMEhas largely contributed to the unsuccessful outcomes of many cancer immunotherapy treatments. Depletion of Treg cells in animal models has shown an increased efficacy of immunotherapy treatments, and therefore, many immunotherapy treatments are now incorporating Treg depletion.[2]

Cancer therapies targeting regulatory T lymphocytes

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Tregs in the TME are abundantly effector Tregs that over-express immunosuppressive molecules such as CTLA-4. Anti-CTLA-4 antibodies cause depletion of Tregs and thus increase CD8+ T cells effective against the tumor. Anti-CTLA-4 antibody ipilimumab was approved for patients with advanced melanoma. Immune-checkpoint molecule PD-1 inhibits activation of both conventional T cells and Tregs and use of anti-PD-1 antibodies may lead to activation and immunosuppressive function of Tregs. Resistance to anti-PD-1-mAb treatment is probably caused by enhanced Treg cell activity. Rapid cancer progression upon PD-1 blockade is called hyperprogressive disease. Therapies targeting Treg suppression include anti-CD25 mAbs and anti-CCR4 mAbs. OX40 agonist and GITR agonists are currently being investigated.[77][79] Therapy targeting TCR signaling is also possible by blocking tyrosine kinases. For example, tyrosine-kinase inhibitor dasatinib is used for treatment of chronic myeloid leukemia and is associated with Treg inhibition.[80]

Molecular characterization

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Similar to other T cells, regulatory T cells develop in the thymus. The latest research suggests that regulatory T cells are defined by expression of the forkhead family transcription factor FOXP3 (forkhead box p3). Expression of FOXP3 is required for regulatory T cell development and appears to control a genetic program specifying this cell's fate.[81] The large majority of Foxp3-expressing regulatory T cells are found within the major histocompatibility complex (MHC) class II restricted CD4-expressing (CD4+) population and express high levels of the interleukin-2 receptor alpha chain (CD25). In addition to the FOXP3-expressing CD4+ CD25+, there also appears to be a minor population of MHC class I restricted CD8+ FOXP3-expressing regulatory T cells. These FOXP3-expressing CD8+ T cells do not appear to be functional in healthy individuals but are induced in autoimmune disease states by T cell receptor stimulation to suppress IL-17-mediated immune responses.[82] Unlike conventional T cells, regulatory T cells do not produce IL-2 and are therefore anergic at baseline.

A number of different methods are employed in research to identify and monitor Treg cells. Originally, high expression of CD25 and CD4 surface markers was used (CD4+CD25+ cells). This is problematic as CD25 is also expressed on non-regulatory T cells in the setting of immune activation such as during an immune response to a pathogen. As defined by CD4 and CD25 expression, regulatory T cells comprise about 5–10% of the mature CD4+ T cell subpopulation in mice and humans, while about 1–2% of Treg can be measured in whole blood. The additional measurement of cellular expression of FOXP3 protein allowed a more specific analysis of Treg cells (CD4+CD25+FOXP3+ cells). However, FOXP3 is also transiently expressed in activated human effector T cells, thus complicating a correct Treg analysis using CD4, CD25 and FOXP3 as markers in humans. Therefore, the gold standard surface marker combination to defined Tregs within unactivated CD3+CD4+ T cells is high CD25 expression combined with the absent or low-level expression of the surface protein CD127 (IL-7RA). If viable cells are not required then the addition of FOXP3 to the CD25 and CD127 combination will provide further stringency. Several additional markers have been described, e.g., high levels of CTLA-4 (cytotoxic T-lymphocyte associated molecule-4) and GITR (glucocorticoid-induced TNF receptor) are also expressed on regulatory T cells, however the functional significance of this expression remains to be defined. There is a great interest in identifying cell surface markers that are uniquely and specifically expressed on all FOXP3-expressing regulatory T cells. However, to date no such molecule has been identified.

The identification of Tregs following cell activation is challenging as conventional T cells will express CD25, transiently express FOXP3 and lose CD127 expression upon activation. It has been shown that Tregs can be detected using an activation-induced marker assay by expression of CD39[83] in combination with co-expression of CD25 and OX40(CD134) which define antigen-specific cells following 24-48h stimulation with antigen.[84][85]

In addition to the search for novel protein markers, a different method to analyze and monitor Treg cells more accurately has been described in the literature. This method is based on DNA methylation analysis. Only in Treg cells, but not in any other cell type, including activated effector T cells, a certain region within the FOXP3 gene (TSDR, Treg-specific-demethylated region) is found demethylated, which allows to monitor Treg cells through a PCR reaction or other DNA-based analysis methods.[86] Interplay between the Th17 cells and regulatory T cells are important in many diseases like respiratory diseases.[87]

Recent evidence suggests that mast cells may be important mediators of Treg-dependent peripheral tolerance.[88]

Epitopes

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Regulatory T cell epitopes ('Tregitopes') were discovered in 2008 and consist of linear sequences of amino acids contained within monoclonal antibodies and immunoglobulin G (IgG). Since their discovery, evidence has indicated Tregitopes may be crucial to the activation of natural regulatory T cells.[89][90][91]

Potential applications of regulatory T cell epitopes have been hypothesised: tolerisation to transplants, protein drugs, blood transfer therapies, and type I diabetes as well as reduction of immune response for the treatment of allergies.[92][93][94][95][96][97][91]

Genetic deficiency

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Genetic mutations in the gene encoding FOXP3 have been identified in both humans and mice based on the heritable disease caused by these mutations. This disease provides the most striking evidence that regulatory T cells play a critical role in maintaining normal immune system function. Humans with mutations in FOXP3 develop a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.[98][99]

The IPEX syndrome is characterized by the development of overwhelming systemic autoimmunity in the first year of life, resulting in the commonly observed triad of watery diarrhea, eczematous dermatitis, and endocrinopathy seen most commonly as insulin-dependent diabetes mellitus. Most individuals have other autoimmune phenomena including Coombs-positive hemolytic anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. The majority of affected males die within the first year of life of either metabolic derangements or sepsis. An analogous disease is also observed in a spontaneous FOXP3-mutant mouse known as "scurfy".

See also

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References

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Regulatory T cells (Tregs) are a specialized subset of CD4⁺ T lymphocytes that express the transcription factor Foxp3 and the high-affinity interleukin-2 receptor alpha chain (CD25), functioning primarily to suppress excessive or dysregulated immune responses and maintain peripheral tolerance to self-antigens. These cells constitute approximately 5-10% of peripheral CD4⁺ T cells and are indispensable for immune homeostasis, preventing autoimmune diseases, limiting chronic inflammation, and modulating responses to infections, tumors, and transplantation. Tregs achieve their suppressive effects through diverse mechanisms, including the secretion of anti-inflammatory cytokines such as IL-10, TGF-β, and IL-35, as well as direct cell-cell interactions that inhibit effector T cells and antigen-presenting cells. Dysfunctions in Treg number, stability, or function have been implicated in a range of pathologies, from immunodeficiencies like IPEX syndrome to enhanced tumor immune evasion. Tregs originate from two main developmental pathways: thymus-derived natural Tregs (tTregs or nTregs), which develop in the under the influence of expression during T cell selection, and peripherally induced Tregs (pTregs or iTregs), which arise from naive CD4⁺ T cells in response to specific environmental cues like TGF-β and in non-lymphoid tissues. The stability of the Treg lineage is tightly regulated by , whose expression is maintained through epigenetic modifications such as at the Treg-specific demethylated region (TSDR) and posttranslational acetylation by enzymes like p300 and Tip60. In addition to and CD25, Tregs are marked by other molecules including CTLA-4, which competes with for B7 ligands on antigen-presenting cells to dampen , and GITR, which modulates their suppressive activity. Beyond , Tregs play pivotal roles in broader immune contexts, such as restraining antitumor immunity by infiltrating tumor microenvironments and suppressing cytotoxic ⁺ T cells, thereby contributing to immune escape in cancers. They also balance responses during chronic infections, where excessive Treg activity can impair clearance, and in transplantation, where enhancing Treg function promotes graft tolerance. Recent insights highlight Treg plasticity, wherein under inflammatory conditions, some Tregs can lose Foxp3 expression and acquire effector-like properties, underscoring their adaptability in dynamic immune environments. Therapeutically, strategies to expand or engineer Tregs—such as low-dose IL-2 administration or Foxp3-targeted —hold promise for treating autoimmune disorders, allergies, and .

Definition and Characteristics

Definition

Regulatory T cells (Tregs) are a specialized subset of + T cells that actively suppress immune responses to maintain immunological self-tolerance, prevent , and limit excessive . These cells are distinguished from conventional T helper cells by their regulatory function, which helps balance immune activation against pathogens while avoiding harmful reactions to self-antigens. The foundational identification of Tregs occurred in , when Sakaguchi et al. demonstrated that a population of + CD25+ T cells in mice could potently suppress autoimmune responses by down-regulating immune activity to both self and non-self antigens, marking a key breakthrough in understanding mechanisms. This discovery revived interest in suppressor T cells, previously dismissed, and established CD25 (the α-chain of the ) as a critical marker for these regulatory cells. The core phenotype of Tregs includes co-expression of , CD25, and the , which is essential for their development and suppressive activity. Functionally, Tregs inhibit effector T cells through mechanisms such as deprivation and direct , suppress proliferation and production via granzyme B-dependent killing, and modulate antigen-presenting cells (APCs) by down-regulating co-stimulatory molecules like those on dendritic cells. Tregs encompass natural thymus-derived cells and peripherally induced variants, both contributing to immune .

Identification Markers

Regulatory T cells (Tregs) are primarily identified by the expression of the FOXP3, which serves as the master regulator of their development and suppressive function. FOXP3 is an intracellular protein essential for Treg lineage commitment and stability, distinguishing Tregs from conventional + T cells. High expression of CD25, the alpha chain of the interleukin-2 receptor (IL-2Rα), is another core marker, enabling Tregs to bind IL-2 with high affinity and supporting their survival and homeostasis through preferential access to this . Additional surface markers refine Treg identification and isolation. Low or absent expression of CD127, the alpha chain of the IL-7 receptor, inversely correlates with levels and suppressive capacity, allowing discrimination of Tregs from activated conventional T cells that upregulate CD25 but retain CD127. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and glucocorticoid-induced TNFR-related protein (GITR) are constitutively expressed on Tregs, contributing to their inhibitory phenotype, though they can also appear on activated non-Tregs. , an family , marks natural (thymic-derived) Tregs with high specificity in steady-state conditions, aiding in the distinction from induced Tregs. Flow cytometry is the standard method for Treg identification, typically involving multicolor panels that combine surface and intracellular staining. A common protocol gates on viable + T cells, then identifies Tregs as CD25highCD127low/-+, often incorporating additional markers like CTLA-4 or for precision. Intracellular detection requires cell fixation and permeabilization, which can alter surface epitopes and necessitate optimized panels to minimize spectral overlap in multicolor setups. Challenges include non-specific staining in activated T cells and variability in CD127 expression, addressed by using 10-12 color panels with viability dyes and compensation controls for accurate enumeration in blood or tissues. Functional validation of identified Tregs relies on suppression assays, where their ability to inhibit responder T cell proliferation confirms regulatory activity. In a typical in vitro assay, carboxyfluorescein succinimidyl ester (CFSE)-labeled conventional CD4+ T cells (responders) are stimulated with anti-CD3/CD28 antibodies and co-cultured with putative Tregs at varying ratios (e.g., 1:1 to 1:16); suppression is quantified by reduced CFSE dilution in responders, indicating halted proliferation. This assay distinguishes bona fide Tregs from FOXP3+ cells lacking suppressive function, with IL-2 supplementation enhancing Treg viability without affecting responders.

Populations and Subtypes

Natural Regulatory T Cells

Natural regulatory T cells (nTregs), also known as thymus-derived regulatory T cells (tTregs), constitute a distinct lineage of FOXP3-expressing + T cells that originate in the during thymocyte development and selection.00108-8) Unlike conventional T cells, nTregs are generated as a committed suppressive population to maintain immune from an early stage.00108-8) This thymic origin ensures their role in innate immune regulation, focusing on surveillance against self-reactive responses. The developmental selection of nTregs occurs in the thymic medulla, where thymocytes with T cell receptors (TCRs) exhibiting high functional for self-antigens presented by medullary thymic epithelial cells or dendritic cells are positively selected into the regulatory lineage.30147-9) This high-avidity recognition, which would typically lead to negative selection and in conventional T cells, instead induces the expression of the FOXP3, marking the commitment to nTreg identity and suppressive function.30147-9) Seminal studies using TCR transgenic models have demonstrated that this process relies on strong, self-antigen-specific interactions to generate a diverse nTreg capable of recognizing a broad array of self-determinants. In peripheral blood, nTregs predominate during steady-state immune surveillance, comprising 5-10% of total + T cells in healthy humans. This proportion reflects their essential function in preventing excessive immune activation and promoting tolerance to self-antigens under homeostatic conditions. nTregs exhibit high stability, characterized by elevated expression of the transcription factors and the surface marker neuropilin-1 (Nrp-1), which signify their thymic derivation and confer resistance to phenotypic conversion. In contrast to induced regulatory T cells, which display greater plasticity in inflammatory environments, nTregs maintain robust expression and suppressive activity.

Induced Regulatory T Cells

Induced regulatory T cells (iTregs), also known as peripheral regulatory T cells (pTregs), are a of regulatory T cells generated from naive + T cells in peripheral tissues outside the , distinguishing them from thymically derived natural regulatory T cells (nTregs) by their extrathymic origin and context-dependent differentiation. Unlike nTregs, which develop during T cell selection in the , iTregs arise in response to environmental cues that promote tolerance to non-self antigens, such as commensal microbes or alloantigens, thereby helping to maintain peripheral immune . iTregs share key identification markers, including and CD25 expression, with nTregs, but their generation relies on specific signaling pathways activated post-thymic migration. The induction of iTregs from naive CD4+ T cells typically requires (TCR) stimulation in the presence of transforming growth factor-β (TGF-β), which drives expression through Smad3-dependent signaling, often synergizing with interleukin-2 (IL-2) to activate STAT5 and enhance Treg stability. Additional factors like all-trans (ATRA), produced by dendritic cells in mucosal environments, further promote iTreg differentiation by upregulating and inhibiting alternative effector pathways, while subimmunogenic doses—such as low-affinity or low-avidity TCR engagement—facilitate conversion without triggering full effector responses. These triggers collectively ensure that iTreg generation occurs under tolerogenic conditions, preventing excessive . iTregs are prominently induced at sites requiring tight immune regulation, such as (GALT), where CD103+ dendritic cells produce ATRA and TGF-β to convert naive T cells into + iTregs that tolerate commensal bacteria. In tumor microenvironments, immunosuppressive factors like TGF-β secreted by cancer cells or stromal elements drive iTreg expansion, contributing to immune evasion by conventional T cells. Similarly, in transplant settings, alloantigen exposure under subimmunogenic conditions, often modulated by immunosuppressive drugs, promotes iTreg induction to mitigate graft rejection. These localized induction sites highlight the adaptability of iTregs to diverse peripheral challenges. Despite their suppressive role, iTregs exhibit plasticity, potentially reverting to proinflammatory effector cells under strong inflammatory signals, such as exposure to interleukin-6 (IL-6), which can redirect Foxp3+ cells toward a Th17-like phenotype by counteracting TGF-β signaling. This instability underscores the context-sensitive nature of iTreg function, where environmental cytokines can destabilize their regulatory identity and exacerbate autoimmunity or chronic inflammation if tolerance mechanisms fail. Such plasticity differentiates iTregs from the more stable nTregs and emphasizes the need for balanced induction conditions to sustain suppression.

Specialized Subtypes

Regulatory T cells exhibit specialized subtypes adapted to specific tissues or immune contexts, characterized by distinct transcription factor expression and functional roles that enhance their suppressive capabilities in localized environments. These subsets often arise through peripheral adaptation of conventional regulatory T cells, integrating environmental cues to maintain tissue homeostasis beyond the core natural and induced populations. RORγt+ regulatory T cells represent a distinct subset enriched in barrier tissues such as the gut and , where they express the RORγt alongside to fine-tune IL-17-mediated responses and promote epithelial barrier integrity. In the intestinal mucosa, these cells suppress excessive Th17-driven inflammation while supporting microbial tolerance, preventing and through targeted inhibition of proinflammatory cytokines.31296-2) In the , peripherally induced RORγt+ regulatory T cells contribute to allergen-specific tolerance, modulating IL-17 production to maintain dermal during allergen exposure. Their development involves microbiota-derived signals that stabilize RORγt expression, ensuring robust barrier protection without compromising overall immune surveillance. Gata3+ regulatory T cells specialize in controlling type 2 immune responses, particularly in mucosal and barrier sites, by expressing the GATA3 to regulate allergic and facilitate tissue repair. These cells produce , an epidermal growth factor-like molecule that promotes epithelial regeneration and in response to type 2 cytokines such as IL-4 and IL-13. In the and , Gata3+ regulatory T cells accumulate during allergic challenges, suppressing infiltration and IgE production while enhancing through amphiregulin-dependent mechanisms.30239-5) This subtype's adaptation underscores their role in balancing protective type 2 immunity against pathological . Tissue-resident regulatory T cells in visceral (VAT) form a specialized population that regulates metabolic through high expression of PPARγ, a that drives their unique transcriptional program. These VAT-resident cells, which constitute up to 50% of + T cells in lean adipose depots, suppress by inhibiting proinflammatory activation and promoting insulin sensitivity via modulation.00244-6) PPARγ deficiency in these cells leads to adipose and systemic metabolic dysfunction, highlighting their essential role in maintaining energy balance. Their accumulation is influenced by age and diet, with high-fat feeding reducing their numbers and exacerbating obesity-related . Tr1 cells constitute a non-FOXP3+ regulatory subset induced by cytokines such as IL-27 and IL-10, distinguished by their potent production of IL-10 and ability to suppress effector T cell responses through bystander mechanisms. Unlike FOXP3+ regulatory T cells, Tr1 cells lack stable FOXP3 expression but exhibit comparable suppressive function via IL-10-dependent inhibition of and secretion.30527-2) They are generated peripherally in response to chronic exposure and play key roles in tolerance to tumors and transplants by promoting IL-10-mediated immune deviation.30527-2) Surface markers like LAG-3 and CD49b reliably identify Tr1 cells, facilitating their therapeutic expansion for immune modulation.30527-2)

Development and Homeostasis

Thymic Origin

Regulatory T cells, also known as natural regulatory T cells (nTregs), originate in the through a specialized developmental pathway that ensures self-tolerance. The process begins with positive selection in the thymic cortex, where double-positive (CD4+CD8+) thymocytes interact with low-affinity self-antigens presented by cortical thymic epithelial cells (cTECs), allowing survival of thymocytes with moderate (TCR) affinity for (MHC) class II molecules. This selection generates CD4+ single-positive (SP) thymocytes that migrate to the thymic medulla for further maturation. In the medulla, Treg commitment occurs when CD4+ SP thymocytes encounter high-affinity self-peptides presented by medullary thymic epithelial cells (mTECs), leading to diversion from the conventional T cell lineage into the Treg fate. Thymic Tregs comprise heterogeneous populations, including + cells derived from strong TCR signals and Helios- cells potentially from weaker signals or peripheral recirculation influences. A critical factor in this process is the (AIRE) protein, expressed in mTECs, which drives promiscuous of thousands of tissue-restricted antigens (TRAs), exposing developing T cells to a broad array of self-antigens to promote central tolerance. AIRE-dependent presentation of these self-antigens directs autoreactive T cells toward the Treg lineage rather than deletion, thereby establishing a repertoire of Tregs capable of suppressing responses to self-tissues. FOXP3, the master defining the Treg lineage, is induced in these medullary precursors through strong TCR signaling combined with interleukin-2 (IL-2) availability, which activates STAT5 via the high-affinity (CD25). This dual signaling threshold ensures that only thymocytes with sufficiently high self-reactivity commit to the Treg fate while avoiding excessive activation that might lead to . Upon maturation, thymic Tregs are exported to the periphery primarily through the bloodstream and lymphatic vessels at the cortico-medullary junction, with occurring approximately 7–10 days after positive selection. These newly exported Tregs initially seed secondary lymphoid organs, particularly lymph nodes, where they establish residence and begin contributing to peripheral immune regulation, facilitated by expression of homing molecules like CD62L.

Peripheral Generation

Peripheral regulatory T cells, also known as induced regulatory T cells (iTregs), arise from the conversion of naive + T cells in extrathymic sites under tolerogenic conditions that promote to self-antigens, commensal microbes, or environmental allergens. This process typically occurs in peripheral lymphoid tissues or mucosal sites, where naive T cells encounter antigens without co-stimulatory signals that would drive pro-inflammatory responses, instead receiving cues that favor suppressive phenotypes. Tolerogenic conditions include the absence of strong inflammatory cytokines and the presence of immunosuppressive factors, enabling the differentiation of Foxp3-expressing iTregs capable of dampening excessive immune activation. A central pathway in iTreg generation involves signaling by the transforming growth factor-β (TGF-β), which, in concert with interleukin-2 (IL-2), drives the conversion of naive +CD25- T cells to +CD25+Foxp3+ iTregs. TGF-β binds to its receptor (TGFβR), activating the canonical Smad signaling pathway wherein receptor-activated Smads (r-Smads 2 and 3) are and form complexes with co-Smad4, translocating to the nucleus to bind conserved non-coding sequence (CNS) elements in the locus, particularly CNS1, thereby activating the promoter and initiating iTreg differentiation. This Smad-dependent activation is essential for de novo expression in peripheral settings, as disruptions in Smad signaling impair iTreg induction while preserving thymic Treg development. IL-2 complements TGF-β by promoting Stat5 , which further stabilizes and supports iTreg and suppressive function. Certain dendritic cell (DC) subsets play a pivotal role in facilitating iTreg generation by presenting antigens in a suppressive context that reinforces tolerogenic signaling. In particular, CD103+ DCs, abundant in gut-associated lymphoid tissues, imprint naive T cells with tolerogenic properties through the production of TGF-β and retinoic acid, which synergize to promote Foxp3 expression and iTreg differentiation in response to mucosal antigens. These DCs migrate to draining lymph nodes, where they present self or harmless foreign antigens without full co-stimulation, thereby directing naive T cells toward an iTreg fate rather than effector responses. The gut microbiome further modulates peripheral iTreg induction via metabolites such as (SCFAs), including butyrate and propionate, produced by fermenting dietary fibers. These SCFAs enhance iTreg generation in the colon by inhibiting histone deacetylases (HDACs), leading to increased at the Foxp3 promoter and heightened expression in naive T cells. Microbiota-derived SCFAs also activate G-protein-coupled receptors (e.g., GPR43) on T cells and DCs, amplifying TGF-β signaling and promoting a tolerogenic environment that boosts colonic iTreg numbers and protects against inflammatory disorders.

Maintenance Mechanisms

Regulatory T cells (Tregs) rely on interleukin-2 (IL-2) signaling through their high-affinity heterotrimeric (composed of IL-2Rα/CD25, IL-2Rβ/CD122, and γc/CD132) to ensure survival and proliferation in the periphery. High CD25 expression on Tregs confers sensitivity to low IL-2 levels, leading to robust that upregulates anti-apoptotic genes like and promotes entry via expression. Disruption of this pathway, such as through IL-2 neutralization, results in rapid Treg loss due to increased and halted division, underscoring its essential role in steady-state . In lymphopenic conditions, where T cell numbers are reduced, Tregs engage in homeostatic proliferation to replenish their compartment and sustain immune . This IL-2-driven process allows Tregs to undergo limited divisions in response to elevated availability and weak self-antigen signals, maintaining their suppressive without converting to effector cells. Experiments transferring purified Tregs into lymphopenic hosts demonstrate their selective expansion, which helps restore . Stable FOXP3 expression, critical for Treg identity and function, is sustained by Treg-specific super-enhancers that integrate developmental and environmental cues. These super-enhancers, established in a Satb1-dependent manner during thymic maturation, remain active in peripheral Tregs to drive high-level transcription and coordinate expression of associated lineage genes. Loss of Satb1 impairs super-enhancer integrity, leading to unstable and diminished Treg maintenance. regulation prevents Treg overaccumulation while supporting longevity, primarily through Bim downregulation. Tregs exhibit constitutively low levels of the pro-apoptotic BH3-only protein Bim compared to conventional T cells, shifting the balance toward and reducing sensitivity to intrinsic pathways. This mechanism ensures controlled turnover, as Bim-deficient Tregs show enhanced persistence but risk excessive numbers, highlighting its role in fine-tuning .

Mechanisms of Suppression

Cell-Cell Contact Mechanisms

Regulatory T cells (Tregs) exert suppressive effects through direct physical interactions with antigen-presenting cells () and effector T cells, primarily via inhibitory receptors that disrupt signaling pathways essential for immune . These contact-dependent mechanisms allow Tregs to form stable conjugates with target cells, limiting T cell priming and proliferation without relying on soluble factors. A prominent example is the consumption of interleukin-2 (IL-2) via the high-affinity alpha chain (CD25) expressed on Tregs, which deprives effector T cells of this essential , thereby inhibiting their proliferation and survival. Observations and have demonstrated that Tregs preferentially cluster around APCs and effector T cells, forming prolonged immune synapses that correlate with suppressed immune responses. For instance, live-cell imaging studies reveal that Tregs dynamically scan APC surfaces and establish multi-cellular clusters, thereby outcompeting conventional T cells for access to APCs and reducing their . A key mechanism involves CTLA-4 on Tregs, which binds with high affinity to and on APCs, preventing these costimulatory ligands from engaging on conventional T cells. This interaction triggers transendocytosis, wherein Tregs internalize and degrade CD80/CD86 from the APC surface, depleting the ligands and impairing APC function. Seminal studies have shown that this process is cell-extrinsic, as CTLA-4-deficient Tregs fail to suppress T cell responses due to inability to remove ligands from APCs, highlighting CTLA-4's role in maintaining . Another contact-dependent pathway is mediated by LAT (linker for activation of T cells) signaling in Tregs, which enables suppression of effector T cells through direct conjugation. Upon forming stable contacts, LAT in Tregs supports conjugate formation and inhibits downstream TCR signaling in effector T cells, such as calcium mobilization required for effector function. This mechanism is independent of CTLA-4 or and requires intact LAT expression in Tregs, as LAT-deficient Tregs exhibit impaired conjugate formation and reduced suppressive capacity . Tregs also utilize and PD-1 to interfere with immune synapse stability between effector T cells and APCs. on Tregs binds and CD112 on APCs, promoting DC maturation arrest via inhibitory signaling, while disrupting costimulatory signaling in cis by competing with CD226 on effector T cells. Concurrently, PD-1 engagement by PD-L1 on APCs stabilizes Treg-APC interactions, preventing effective formation for effector T cell activation. Studies demonstrate that signaling in Tregs enhances their suppressive phenotype, with TIGIT-deficient Tregs showing diminished control over antitumor immunity .

Secreted Factors

Regulatory T cells (Tregs) exert immunosuppressive effects through the secretion of various soluble factors, including cytokines and cytolytic molecules, which modulate the activity of effector immune cells and promote tolerance. These secreted mediators enable Tregs to dampen inflammatory responses in a non-contact-dependent manner, contributing to immune homeostasis and prevention of autoimmunity. Transforming growth factor-β (TGF-β), particularly the TGF-β1 isoform, is a key cytokine secreted by Tregs that promotes immune tolerance by inhibiting the proliferation and differentiation of pro-inflammatory T cells, such as Th1 and Th17 subsets, while enhancing the generation of induced Tregs in peripheral tissues. TGF-β also plays a role in controlling fibrosis by regulating extracellular matrix production in chronic inflammatory settings. In addition to its suppressive functions, TGF-β contributes to the peripheral induction of Tregs from naive CD4⁺ T cells under tolerogenic conditions. Interleukin-10 (IL-10), another major produced by Tregs, suppresses immune responses by inhibiting the production of pro-inflammatory s like IL-12, TNF-α, and IFN-γ from antigen-presenting cells and effector T cells. IL-10 by Tregs is crucial for limiting excessive at mucosal surfaces and preventing tissue damage during immune challenges. This also supports Treg stability and function through . Interleukin-35 (IL-35), a heterodimeric composed of the EBI3 and IL-12α subunits, is selectively produced by activated Tregs and expands their suppressive capacity by directly inhibiting T and promoting the conversion of conventional T cells into IL-35-secreting regulatory cells, a known as infectious tolerance. IL-35 enhances Treg-mediated suppression in autoimmune and inflammatory models by downregulating effector production and inducing in target cells. Unlike other Treg cytokines, IL-35 expression is tightly linked to Foxp3⁺ Treg identity and is essential for their maximal regulatory activity . Tregs also secrete and perforin, components of cytotoxic granules, to eliminate effector immune cells through a perforin-dependent pore formation that allows entry, triggering activation and in target cells such as activated ⁺ T cells and natural killer cells. This cytolytic mechanism is particularly important for Treg suppression of anti-tumor immunity and control of excessive effector responses in transplantation settings. secretion by Tregs occurs independently of classic recognition and relies on high-affinity interactions with target cells.

Environmental Modulation

Regulatory T cells (Tregs) modulate the immune microenvironment by generating immunosuppressive metabolites, particularly through the production of . Tregs express the ectonucleotidases (also known as ) and (also known as ), which sequentially hydrolyze extracellular ATP to ADP, AMP, and finally . This acts on adenosine receptors (ADORA2A) expressed on effector T cells and other immune cells, inhibiting their activation, proliferation, and production. This mechanism is critical in inflamed tissues and tumor microenvironments, where elevated ATP from is converted into , creating a localized suppressive niche. In addition to adenosine signaling, Tregs impose metabolic constraints on effector cells by limiting nutrient availability, including through CD73-mediated consumption of AMP, which indirectly deprives the microenvironment of substrates needed for effector . generated via this pathway suppresses glycolytic flux in effector T cells by elevating intracellular cAMP levels, which inhibits signaling and shifts metabolism away from rapid ATP production required for proliferation and effector functions. This results in reduced and lactate production in target cells, favoring Treg dominance in nutrient-scarce environments. Tregs also transfer cyclic AMP (cAMP) directly to effector T cells via connexin-dependent gap junctions, amplifying suppression without requiring secreted factors. High intracellular cAMP in Tregs activates (PKA), which, upon transfer, disrupts downstream signaling in recipients, including inhibition of and AP-1 pathways essential for effector responses. This intercellular exchange is contact-dependent and enhances the metabolic quiescence of nearby cells. In visceral , specialized Treg populations influence to maintain systemic insulin sensitivity. These adipose-resident Tregs express high levels of PPAR-γ, a that promotes oxidation and uptake via , allowing Tregs to adapt to the lipid-rich niche while suppressing pro-inflammatory macrophages and adipocytes. This shift reduces lipid spillover into circulation and ectopic deposition, thereby preventing ; depletion of these Tregs in obese models exacerbates metabolic dysfunction.

Molecular Features

Key Transcription Factors

The forkhead box P3 () transcription factor acts as the primary lineage specifier for regulatory T cells (Tregs), directing their differentiation from conventional CD4⁺ T cells and enforcing suppressive identity through direct binding to target gene enhancers. expression is induced by T cell receptor signaling in combination with transforming growth factor-β, leading to stable Treg commitment and prevention of effector T cell conversion. functions by forming complexes with other transcription factors, notably interacting with nuclear factor of activated T cells (NFAT) to cooperatively bind DNA and repress proinflammatory cytokine genes such as interleukin-2 (IL-2). Similarly, associates with NF-κB subunits, including (p65), to inhibit NF-κB-driven transcription of effector cytokines like interferon-γ and , thereby dampening activation. Mutations in disrupt these interactions, leading to loss of Treg suppressive capacity and conditions like immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, as detailed in genetic studies. Additional transcription factors support FOXP3-dependent Treg stability and function. Runx1 (also known as AML1) physically interacts with FOXP3 via its Runt domain, enhancing FOXP3 binding to target promoters and maintaining high-level expression to prevent lineage instability and autoimmune phenotypes . Foxo1, a forkhead box O family member, promotes Treg homeostasis by directly transactivating and repressing genes associated with T helper 17 or T helper 1 differentiation, ensuring long-term suppressive potency under inflammatory conditions. In effector Tregs, Blimp-1 (encoded by ) drives IL-10 production by binding to the Il10 promoter and coordinating with c-Maf, which is critical for limiting excessive without altering core Treg identity. Context-specific factors further refine Treg transcriptional programs. In intestinal Tregs, retinoic acid receptor-related orphan receptor γt (RORγt) co-expression with antagonizes Th17 cell differentiation by competing for shared enhancers, thereby balancing microbial tolerance and inflammatory suppression in the gut mucosa. In Th2-skewed environments, GATA3 expression in Tregs enhances their tissue-resident properties and induces (Areg) secretion, a that promotes epithelial repair independently of canonical suppression.

Epigenetic Regulation

Epigenetic modifications play a crucial role in establishing and maintaining the stable suppressive of regulatory T cells (Tregs) by ensuring heritable control of . Central to this is the demethylation of the Treg-specific demethylated region (TSDR), a conserved non-coding sequence (CNS2) within the locus, which promotes stable FOXP3 expression essential for Treg identity. This demethylation, primarily mediated by TET enzymes such as TET2, occurs specifically in mature Tregs and correlates with resistance to inflammatory reprogramming, thereby preventing loss of suppressive function. Histone acetylation further contributes to Treg stability by modulating accessibility at key regulatory loci. The TIP60 interacts with to acetylate histones and FOXP3 itself, enhancing transcriptional activation of suppressive genes and reducing Treg plasticity under inflammatory conditions. Conversely, inhibitors can alter this balance, promoting Treg instability and conversion to effector phenotypes, highlighting the dynamic role of acetylation in phenotypic fidelity. MicroRNAs (miRNAs) provide an additional layer of epigenetic control by post-transcriptionally regulating inflammatory pathways in Tregs. Notably, miR-146a, highly expressed in Tregs, suppresses pro-inflammatory signaling by targeting TRAF6 and IRAK1, thereby reinforcing the cells' tolerogenic function and limiting excessive immune activation. The enhancer landscape in Tregs is characterized by unique, accessible regions that drive lineage-specific gene expression, often pre-established in precursor cells and refined by binding. These Treg-specific enhancers, including multiple CNS elements at the locus, ensure coordinated activation of suppressive programs while maintaining epigenetic stability across cell divisions. Such conserved non-coding sequences facilitate robust Treg by integrating signals from the microenvironment to sustain -dependent suppression.

Surface Epitopes

Regulatory T cells (Tregs) are characterized by distinct surface markers that facilitate their identification, activation, and suppressive function. The high-affinity (CD25, also known as ) is constitutively expressed on Tregs, enabling preferential responsiveness to low concentrations of IL-2 for survival and , while distinguishing them from activated conventional T cells. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), upregulated on Tregs, binds and on antigen-presenting cells with higher affinity than , thereby outcompeting effector T cells for costimulatory signals and transducing inhibitory signals to dampen immune activation. Glucocorticoid-induced TNFR-related protein (GITR, encoded by TNFRSF18) is another hallmark surface receptor on Tregs, which upon ligation can modulate their suppressive activity—enhancing proliferation in some contexts while reducing suppression in others—thus serving as a bidirectional regulator of Treg function. Additional surface epitopes include (PD-1), which contributes to Treg-mediated inhibition in chronic inflammation and tumors by engaging , and low expression of CD127 (IL-7 receptor alpha chain), reflecting their reduced dependence on IL-7 for maintenance compared to conventional T cells. These markers collectively enable flow cytometric isolation of Tregs (e.g., CD4⁺ CD25⁺ ⁺) and underpin therapeutic strategies targeting Treg modulation.

Role in Immune Regulation

Self-Tolerance

Regulatory T cells (Tregs) are essential for establishing and maintaining self-tolerance, preventing by suppressing immune responses against self-antigens through both central and peripheral mechanisms. In central tolerance, thymus-derived natural Tregs (nTregs) arise from T cells with high-affinity T cell receptors (TCRs) for self-peptides presented by (MHC) molecules, enabling them to recognize and control self-reactive lymphocytes that partially escape negative selection. In the periphery, induced Tregs (iTregs) can develop from naive + T cells under tolerogenic conditions, further reinforcing tolerance to self-antigens. This dual origin ensures comprehensive oversight of potentially autoreactive T cells throughout the . A primary function of Tregs in self-tolerance involves the suppression of autoreactive T cells that evade thymic deletion and enter the peripheral repertoire. These self-reactive clones, if activated, could initiate autoimmune responses, but Tregs actively inhibit their proliferation and differentiation into effector cells via contact-dependent and cytokine-mediated pathways. For instance, Tregs express CTLA-4 to downregulate costimulatory molecules on antigen-presenting cells, thereby impairing the of autoreactive T cells, while secreting cytokines such as TGF-β and IL-10 to dampen their effector functions. Experimental depletion of Tregs in models rapidly leads to multi-organ , underscoring their indispensable role in controlling these escaped clones. Tregs also patrol secondary lymphoid organs, particularly lymph nodes, to inhibit the priming of self-reactive T cell clones by dendritic cells presenting self-antigens. Enriched with homing receptors like CCR7 and CD62L, Tregs migrate to these sites where they compete with naive T cells for , preventing the initiation of autoreactive responses. This surveillance mechanism is antigen-specific, allowing Tregs to proliferate locally in response to self-antigens and sustain long-term suppression. Furthermore, Tregs contribute to peripheral self-tolerance by promoting anergy and deletion of self-specific effector T cells. Upon encountering self-antigens, Tregs can induce anergy—a state of unresponsiveness—in autoreactive effectors through deprivation or direct contact, while also triggering their via and perforin pathways. This active elimination helps eliminate activated self-reactive cells before they cause tissue damage. In healthy immunity, Tregs maintain a delicate balance with effector T cell responses, ensuring robust defense against pathogens without compromising self-tolerance. Persistent exposure to self-antigens favors Treg expansion over effectors, as seen in models where self-antigen persistence leads to effector inactivation and Treg dominance in tissues, resolving while preserving immune competence. This equilibrium prevents excessive effector activity that could cross-react with self-tissues, highlighting Tregs' role as key arbiters of immune homeostasis.

Tolerance to Microbiota

Regulatory T cells (Tregs) play a pivotal role in maintaining immune at mucosal barriers by promoting tolerance to commensal in the gut and , preventing aberrant inflammatory responses to symbiotic microbes. In the intestinal , microbiota-specific Tregs are highly enriched, comprising a significant proportion of CD4+ T cells and exhibiting antigen specificity for bacterial components, which enables localized suppression of pro-inflammatory effector cells. Similarly, in the , a distinct of Tregs expands during neonatal to establish long-term tolerance to commensal such as . This enrichment ensures that immune responses remain balanced, allowing beneficial microbial communities to thrive without triggering . A key mechanism of Treg induction involves microbial metabolites, exemplified by polysaccharide A (PSA) from Bacteroides fragilis, a prominent gut commensal. PSA signals through Toll-like receptor 2 on antigen-presenting cells, leading to the differentiation and expansion of Foxp3+ Tregs that produce anti-inflammatory cytokines like IL-10, thereby fostering tolerance to the broader microbiota. Gut-specific RORγt+ Tregs, adapted to the colonic environment, further enhance this process by responding to microbial cues. These induced Tregs accumulate in the lamina propria, where they directly suppress T helper cell responses to prevent overzealous immunity against harmless antigens. Tregs are essential for averting dysbiosis-induced , such as in models, where their depletion leads to microbial imbalance and severe mucosal damage. By maintaining composition through suppression of Th17-driven responses, Tregs preserve barrier and limit bacterial translocation that could exacerbate . Adoptive transfer of microbiota-specific Tregs has been shown to ameliorate in experimental settings, highlighting their therapeutic potential in dysbiosis-associated disorders. Tregs engage in dynamic cross-talk with (ILCs) and dendritic cells (DCs) to reinforce mucosal tolerance. ILC3s, enriched in the gut, collaborate with Tregs by producing IL-2, which sustains Treg survival and function while selecting for -reactive clones to promote commensal-specific suppression. DCs, in turn, present microbial antigens in a tolerogenic manner, often via production, to induce Treg differentiation and amplify their suppressive activity at barrier sites. This interplay ensures coordinated regulation of innate and adaptive immunity against the .

Involvement in Diseases

Autoimmune and Inflammatory Diseases

Regulatory T cells (Tregs) play a crucial protective role in preventing and chronic by suppressing aberrant immune responses against self-antigens and maintaining immune . Deficiencies in Treg numbers or function have been implicated in the of several autoimmune diseases, where impaired suppression allows autoreactive T cells to drive tissue damage. For instance, in (T1D), Tregs exhibit reduced suppressive capacity despite normal frequencies, failing to control β-cell-specific autoreactive + and + T cells, leading to pancreatic destruction. Similarly, in (MS), Treg dysfunction contributes to the failure of immune regulation in the , promoting Th1- and Th17-mediated demyelination through spreading and inadequate suppression of pathogenic clones. In (RA), decreased Treg frequencies in peripheral blood and , coupled with impaired function due to the inflammatory milieu, exacerbate by allowing unchecked T cell and activation. In (IBD), particularly and , Tregs accumulate in the intestinal but display reduced suppressive capacity, contributing to persistent mucosal inflammation. This dysfunction arises from defects in Treg trafficking to the gut, increased in inflamed tissues, and resistance of effector T cells to Treg-mediated suppression, often linked to insensitivity to TGF-β signaling. Studies in IBD patients reveal that Tregs fail to effectively inhibit pro-inflammatory Th1 and Th17 responses, resulting in an imbalance that perpetuates chronic . Therapeutic strategies aimed at restoring Treg function have shown promise in preclinical and clinical settings for autoimmune and inflammatory diseases. Low-dose interleukin-2 (IL-2) complexes selectively expand Tregs by preferentially binding to the high-affinity on these cells, enhancing their survival and suppressive activity without promoting effector T cell proliferation. Clinical trials in T1D, MS, RA, and IBD have demonstrated safe Treg expansion with low-dose IL-2 (e.g., 0.33–1 million IU/day), leading to improved clinical scores in some cases, such as reduced disease activity in RA and , though β-cell preservation in T1D remains variable. Ongoing phase I/II trials continue to evaluate IL-2-based approaches for broader efficacy in restoring . A key challenge in Treg-mediated regulation is their plasticity under inflammatory conditions, where Tregs can convert into pro-inflammatory Th17-like cells, undermining suppression and exacerbating . This inflammation-induced plasticity is driven by cytokines such as IL-6 and IL-1β, which activate and HIF-1α/ pathways, destabilizing expression and promoting IL-17 production despite residual Treg markers. In RA and IBD, such conversions are prominent in synovial and mucosal tissues, where local inflammation shifts Tregs toward pathogenic phenotypes, contributing to disease progression. Epigenetic factors, including loss of TET proteins, further enhance this instability, highlighting the need for therapies that stabilize Treg identity to sustain long-term tolerance.

Infectious Diseases

Regulatory T cells (Tregs) exhibit a dual role in infectious diseases, where they limit excessive immune-mediated tissue damage while potentially hindering pathogen clearance. In human immunodeficiency virus () infection, Tregs suppress hyperactivation of CD8+ T cells, reducing markers of immune exhaustion such as expression, which correlates with improved patient survival in advanced stages. Similarly, in (TB), Tregs maintain immunological tolerance by inhibiting effector T cell responses at infection sites, thereby mitigating granuloma-associated pathology in tuberculosis-infected lungs. However, this suppressive function can impair viral or bacterial elimination; for instance, in chronic lymphocytic choriomeningitis virus (LCMV) infection, expanded Tregs promote CD8+ T cell exhaustion through IL-10 and TGF-β signaling, sustaining viral persistence and preventing clearance, as evidenced by partial restoration of antiviral responses upon Treg depletion. During acute infections, Tregs expand rapidly through antigen-specific induction, often in response to pathogen-derived antigens presented in lymphoid tissues. This process involves conversion of conventional + T cells into induced Tregs (iTregs) via TGF-β and IL-2 signaling, leading to localized suppression at sites of high to balance inflammation and control. In acute retroviral infections like or LCMV, this expansion is confined to infected organs, where antigen-specific Tregs attenuate effector responses without broadly compromising immunity. Such dynamics are particularly evident in respiratory infections, where antigen-specific Tregs limit influx and release, preventing excessive damage while allowing initial containment. In severe acute respiratory syndrome coronavirus 2 () infection causing , virus-induced Tregs play a protective role by dampening storms through production of IL-10 and TGF-β, which inhibit pro-inflammatory s like IL-6 and TNF-α. Although Treg frequencies decline in severe cases, correlating with heightened and Th17/Treg imbalance, their suppressive activity in milder infections helps resolve hyper and promotes tissue repair. Recent studies as of 2024 also implicate persistent Treg dysfunction in , contributing to chronic and fatigue through sustained Th17 skewing. This mechanism underscores Tregs' potential in therapeutic strategies, such as low-dose IL-2 to enhance Treg function and mitigate storm-related pathology. Parasitic helminth infections, such as those caused by or Nippostrongylus species, robustly promote iTreg differentiation for establishing long-term host tolerance, enabling parasite survival while averting severe allergic or inflammatory responses. Helminth-derived products, including excretory-secretory antigens, induce Foxp3+ iTregs in the gut mucosa via dendritic cell-mediated TGF-β and signaling, leading to sustained suppression of Th2-driven immunity and reduced recruitment. This tolerance extends beyond the infection, as helminth-induced Tregs exhibit bystander suppression of unrelated inflammatory pathways, contributing to the observed protective effects against allergic diseases in endemic populations.

Cancer

Regulatory T cells (Tregs) contribute to tumor progression by infiltrating the and dampening anti-tumor immunity. High levels of tumor-infiltrating FOXP3+ Tregs are associated with poor prognosis in multiple cancers, including and . In , elevated Treg infiltration correlates with reduced patient survival, as these cells foster an immunosuppressive environment that limits effective anti-tumor responses. Similarly, in , increased intratumoral FOXP3+ Tregs predict worse clinical outcomes by inhibiting effector immune cell function. Treg recruitment to tumors is driven by specific chemokine axes, notably the CCL22-CCR4 pathway, which selectively attracts CCR4-expressing Tregs to the site of malignancy. Tumor cells and associated stromal elements secrete CCL22, promoting Treg migration and accumulation in the immunosuppressive niche, as observed in ovarian carcinoma and other solid tumors. Hypoxic conditions within the tumor microenvironment further enhance Treg infiltration and stability by inducing FOXP3 expression through hypoxia-inducible factor-1α (HIF-1α)-mediated transcriptional regulation. This hypoxia-driven mechanism amplifies Treg suppressive activity, reinforcing immune tolerance in oxygen-deprived tumor regions. Infiltrating Tregs exert their pro-tumor effects by suppressing key anti-tumor effectors, including CD8+ T cells and natural killer (NK) cells. Through mechanisms such as IL-10 and TGF-β secretion, CTLA-4-mediated competition for co-stimulatory ligands, and /perforin-dependent cytotoxicity, Tregs inhibit CD8+ T cell proliferation and cytotoxicity while impairing NK cell activation and tumor cell lysis. This targeted suppression creates a barrier to effective immune surveillance, allowing tumor growth and . Treg populations in tumors display significant heterogeneity, encompassing thymus-derived natural Tregs with broad suppressive functions and peripherally induced tumor antigen-specific Tregs that exhibit enhanced potency within the . Tumor-specific Tregs, often enriched in the tumor bed, demonstrate heightened expression of suppressive molecules and adapt to local cues like , distinguishing them from non-specific Tregs that provide generalized tolerance. This diversity enables Tregs to fine-tune tailored to tumor-specific challenges.

Pregnancy and Reproduction

Regulatory T cells (Tregs) play a in establishing maternal-fetal tolerance during early , particularly through the expansion of paternal antigen-specific Tregs around the time of implantation. In murine models, these antigen-specific Tregs proliferate in uterine-draining nodes immediately prior to implantation, enabling the suppression of maternal immune responses against paternal antigens expressed by the developing . This expansion is driven by the persistence of paternal antigens in the maternal system, which promotes Treg accumulation and differentiation to prevent rejection of the semi-allogeneic . Seminal fluid also contributes to this process by activating Tregs in draining nodes, facilitating tolerance to the implanting . In the , the mucosal layer of the pregnant , Tregs accumulate and actively suppress alloreactive maternal T cell responses to maintain immune . Decidual Tregs exert their suppressive effects through the of cytokines such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), which inhibit effector T and promote a tolerogenic environment at the maternal-fetal interface. For instance, programmed death-1 high (PD-1hi) decidual Tregs specifically suppress T effector responses in an IL-10-dependent manner, ensuring that inflammatory cascades do not disrupt . Additionally, TGF-β produced by these Tregs modulates the of other decidual immune cells, such as uterine natural killer cells and macrophages, further reinforcing tolerance. Dysfunction or reduction in Treg numbers and suppressive capacity is strongly associated with , a hypertensive disorder of characterized by placental ischemia and maternal endothelial damage. Women with exhibit decreased circulating and decidual ^+ Treg frequencies compared to healthy pregnant controls, correlating with heightened inflammatory responses. This reduction impairs Treg-mediated suppression, leading to an imbalance favoring pro-inflammatory Th17 cells and exacerbated alloreactivity against fetal antigens. Functional exhaustion of Tregs, marked by elevated expression of (PD-1), further diminishes their regulatory activity in preeclamptic placentas, contributing to disease pathogenesis. Studies also link reduced fetal thymic Treg output in to maternal metabolic alterations, such as low serum levels, underscoring the systemic impact on tolerance. Following delivery, the expanded Treg pool contracts postpartum, which is linked to an increased risk of flares in susceptible women. This physiological contraction restores baseline immune surveillance but can unmask latent , particularly in conditions like and , where postpartum relapse rates rise sharply. The decline in pregnancy-induced Tregs disrupts the Th2/Treg balance established during , promoting Th1/Th17-driven and elevating susceptibility in the early . While some fetal-specific memory Tregs persist to confer protection in subsequent pregnancies, the overall postpartum Treg reduction heightens vulnerability to immune dysregulation.

Neurodegenerative Diseases

Regulatory T cells (Tregs) play a protective role in neurodegenerative diseases by modulating neuroinflammation and maintaining central nervous system (CNS) homeostasis, though their dysfunction or depletion exacerbates pathology in conditions such as amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD). In these disorders, Tregs infiltrate the CNS or reside in meningeal compartments to suppress excessive immune responses that contribute to neuronal damage. Reduced Treg numbers or impaired suppressive function correlate with accelerated disease progression, highlighting their therapeutic potential. In , patients exhibit diminished Treg frequencies and suppressive capacity, which inversely correlate with disease progression rates, particularly in fast-progressing cases where dysfunctional Tregs fail to curb . Longitudinal studies confirm stable but phenotypically altered Treg levels over time, with increases in CD39+ Tregs potentially reflecting compensatory mechanisms, though no direct link to functional decline in ALSFRS-R scores was observed. Therapeutic interventions targeting Tregs, such as low-dose interleukin-2 (IL-2) combined with autologous Treg infusions, have demonstrated safety and tolerability in phase 2a trials, enhancing Treg numbers and suppressive function by up to 22.8% while slowing progression in a subset of participants. The MIROCALS trial further supports IL-2's role in expanding Tregs as an add-on to , improving survival and function without significant adverse effects. Tregs also suppress in experimental autoimmune (EAE), a preclinical model of MS, by inhibiting pathogenic Th17 cell signaling and reducing CNS infiltration of proinflammatory + T cells. Gene therapy-induced myelin-specific Tregs effectively reverse EAE symptoms, abrogating inflammation and restoring neurological function even in established disease. Spinal delivery of Tregs or their derived IL-35 further attenuates EAE-associated pain and by promoting myelination and limiting glial activation. Meningeal Tregs represent a distinct CNS-resident population that crosses the to preserve integrity, clustering near dural sinuses to restrain IFN-γ-producing lymphocytes and prevent hippocampal disruption. Depletion of these Tregs triggers T cell infiltration, glial reactivity, and cognitive deficits, mirroring age-related and neurodegenerative changes. In , amyloid-β-specific Tregs attenuate by reducing plaque burden, restoring , and enhancing , as shown in adoptive transfer models where they outperform polyclonal Tregs. Ex vivo-expanded human Tregs similarly suppress and alleviate AD-like features in vivo.

Genetic and Functional Deficiencies

Genetic Mutations

Mutations in the gene, which encodes a master essential for regulatory T cell (Treg) development and function, cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, an X-linked recessive disorder characterized by severe, early-onset . These mutations lead to absent or dysfunctional FOXP3+ Tregs, resulting in uncontrolled effector T cell responses and multi-organ . Clinical features of IPEX syndrome include intractable enteropathy with villous atrophy, autoimmune endocrinopathies such as and , eczematous dermatitis, and elevated serum IgE levels, often manifesting in infancy and leading to high mortality if untreated. Beyond FOXP3, germline mutations in other genes disrupt Treg homeostasis and function. Heterozygous loss-of-function mutations in CTLA-4, encoding a key inhibitory receptor constitutively expressed on Tregs, cause CTLA-4 haploinsufficiency with autoimmune infiltration of lungs, gastrointestinal tract, and endocrine organs, alongside hypogammaglobulinemia and recurrent infections due to impaired Treg-mediated suppression. Similarly, autosomal recessive mutations in STAT5B, a critical mediator of IL-2 signaling required for Treg survival and FOXP3 expression, result in combined immunodeficiency with reduced Treg numbers, lymphopenia, and autoimmunity including eczema, thyroid disease, and growth hormone insensitivity. These defects highlight the genetic vulnerability of Treg pathways to inherited disruptions, leading to immunodysregulation polyendocrinopathy syndromes. Diagnosis of these genetic Treg deficiencies relies on targeted next-generation sequencing to identify pathogenic variants in FOXP3, CTLA-4, or STAT5B, confirmed by segregation analysis in families. Functional assays, such as to quantify + Tregs and assess their suppressive capacity , alongside phospho-STAT5 evaluation in response to IL-2 stimulation, provide corroborative evidence of impaired Treg activity. Early genetic confirmation is crucial for guiding as a curative approach.

Acquired Dysfunctions

Acquired dysfunctions of regulatory T cells (Tregs) arise from environmental factors, chronic , pharmacological interventions, or disruptions in host-microbe interactions, leading to impaired suppressive capacity without underlying genetic alterations. These impairments can destabilize immune , promoting excessive or . Key mechanisms include the loss of the , which is essential for Treg identity and function, often triggered by external signals that alter epigenetic stability or metabolic pathways. Inflammatory environments can induce Treg instability by promoting the degradation or downregulation of . Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) have been shown to trigger FOXP3 protein degradation through interactions with cellular factors like DBC1, thereby reducing Treg suppressive activity. Additionally, antigen-driven activation in inflamed tissues, such as the during autoimmune responses, selectively destabilizes FOXP3 expression in autoreactive Tregs, leading to their conversion into pro-inflammatory effector cells. This plasticity is exacerbated under chronic inflammation, where cytokines like IL-6 upregulate inhibitor of DNA binding 2 (Id2), further promoting loss of FOXP3 and Treg reprogramming toward T helper-like phenotypes. Aging contributes to acquired Treg dysfunction through progressive declines in suppressive function, despite increases in Treg frequencies. In elderly individuals, naturally occurring Tregs (nTregs) accumulate in peripheral blood and lymphoid organs, but their ability to suppress pro-inflammatory responses, such as IL-17 production by + T cells, is significantly impaired, potentially driving age-related . Inducible Tregs (iTregs), which are generated in response to environmental cues, show reduced numbers and diminished induction capacity in aged hosts, linked to altered subset distribution and metabolic changes that favor effector over regulatory phenotypes. This functional decline correlates with broader immune , where Tregs fail to adequately control chronic low-grade known as inflammaging. Pharmacological agents, particularly calcineurin inhibitors like cyclosporine A (CsA), can inhibit de novo Treg generation and impair existing Treg function. CsA blocks activity, preventing nuclear factor of activated T cells (NFAT) and subsequent binding to the promoter, which is crucial for stable Treg differentiation from naïve + T cells. studies demonstrate that CsA not only abrogates induction independently of interleukin-2 signaling but also enhances pro-inflammatory secretion (e.g., IL-2 and IFN-γ) by Tregs, thereby reducing their suppressive efficacy. These effects are dose-dependent, with higher doses more potently disrupting Treg development while low doses may paradoxically support expansion in certain contexts. Microbiome dysbiosis, characterized by imbalances in gut microbial communities, leads to impaired peripheral Treg induction by disrupting metabolite production essential for Treg differentiation. Reduced levels of short-chain fatty acids (SCFAs), such as butyrate and propionate, derived from microbial fermentation, fail to inhibit histone deacetylases (HDACs), resulting in decreased FOXP3 expression and diminished iTreg generation in the colonic mucosa. Similarly, dysbiosis lowers secondary bile acids like iso-deoxycholic acid, which normally promote Treg induction via farnesoid X receptor (FXR) and vitamin D receptor (VDR) signaling, thereby exacerbating inflammatory conditions through unchecked effector T cell responses. This impairment creates a vicious cycle, as dysfunctional Tregs further alter microbial composition, perpetuating dysbiosis.

Therapeutic Targeting

Treg Expansion Therapies

Regulatory T cell (Treg) expansion therapies aim to increase Treg numbers and function to restore in autoimmune diseases and prevent allograft rejection in transplantation settings. These approaches leverage the immunosuppressive properties of Tregs to suppress pathogenic effector responses without broad . Strategies include expansion for adoptive transfer and stimulation to selectively amplify endogenous Tregs. Ex vivo expansion of Tregs typically involves isolating CD4+CD25+FOXP3+ cells from peripheral blood, followed by culture with interleukin-2 (IL-2) to promote proliferation while maintaining suppressive function. The addition of rapamycin () during expansion enhances Treg stability by inhibiting signaling, reducing effector T cell contamination, and preserving FOXP3 expression, leading to more potent and persistent Tregs upon adoptive transfer. In nonhuman models, combining ex vivo-expanded Tregs with post-infusion low-dose IL-2 and rapamycin extended Treg by nearly 10-fold compared to controls, demonstrating improved persistence without toxicity. Clinical-grade processes using this protocol have enabled the production of billions of stable Tregs under conditions for human use. In vivo expansion primarily utilizes low-dose IL-2, which preferentially stimulates CD25-high Tregs over effector T cells due to their higher affinity. In a phase I/II trial for steroid-refractory chronic (GVHD), low-dose IL-2 (up to 1×10^6 IU/m²) expanded circulating Tregs by over eightfold within four weeks, increased the Treg:conventional T cell ratio more than fivefold, and induced partial clinical responses in 52% of patients, allowing dose reductions of up to 100% with a favorable safety profile limited to reversible injection-site reactions. Similarly, in a phase 1/2 randomized trial for recent-onset , low-dose IL-2 (0.3×10^6 to 1.5×10^6 IU/m²) dose-dependently increased Treg numbers up to 10-fold, preserved beta-cell function as measured by levels, and was well-tolerated without serious adverse events. Ongoing trials combine in vivo IL-2 with ex vivo-expanded Tregs, such as in chronic GVHD, where donor Tregs followed by low-dose IL-2 were safe and supported Treg persistence. Chimeric antigen receptor (CAR)-Treg engineering redirects Tregs to specific for targeted suppression, combining CAR with Treg's tolerogenic potential. CAR-Tregs expressing antigen-specific receptors, such as against HLA-A2 for transplantation or autoantigens like in models, exhibit enhanced migration to target tissues and antigen-specific suppression of effector responses and without . Preclinical studies show CAR-Tregs prevent allograft rejection and ameliorate autoimmune inflammation more effectively than polyclonal Tregs, with stable expression and infectious tolerance induction. As of 2025, phase II/III trials of Treg expansion therapies report consistent safety, with mild adverse events like transient flu-like symptoms or injection-site reactions, and no evidence of tumorigenesis or opportunistic infections. In , phase II trials of ex vivo-expanded polyclonal Tregs demonstrated feasibility, with infused cells persisting for months and associating with reduced needs, though larger efficacy endpoints remain under evaluation. A phase II trial of autologous expanded Tregs in showed safety but no significant preservation of beta-cell function with a single dose, highlighting the need for optimized dosing or antigen-specific approaches. For GVHD prophylaxis post-hematopoietic transplantation, phase II data from low-dose IL-2 trials indicate accelerated Treg reconstitution and lower severe GVHD incidence compared to standard care. CAR-Treg therapies are in early phase I/II stages, with interim data from HLA-specific CAR-Tregs in transplant recipients showing no dose-limiting toxicities and detectable Treg expansion at transplant sites. Overall, these trials underscore the promise of Treg expansion for tolerance induction, with over 60 active studies worldwide focusing on and transplantation.

Depletion Strategies in Cancer

Regulatory T cells (Tregs) in the suppress anti-tumor immune responses, prompting the development of depletion strategies to enhance effector T cell activity and improve outcomes in cancer. These approaches aim to selectively reduce Treg populations, thereby alleviating without broadly compromising immune function. Key methods include antibody-based targeting, chemotherapeutic agents at low doses, and viral therapies that disrupt Treg-mediated suppression. Anti-CD25 monoclonal antibodies, such as , have been investigated for transient Treg depletion due to the high expression of CD25 ( alpha chain) on Tregs compared to effector T cells. binds CD25, leading to (ADCC) and (CDC) that selectively eliminates CD25+ Tregs in peripheral blood and tumors, with depletion observed within days and recovery over weeks. In a phase I clinical trial for cancer patients, administration resulted in up to 70% reduction in circulating Tregs, enhancing vaccine-induced immune responses without significant effector T cell loss. Fc-optimized anti-CD25 antibodies further improve intratumoral Treg depletion by enhancing Fcγ receptor binding, increasing the effector-to-Treg ratio and promoting tumor regression in preclinical models. Novel agents like vopikitug (RG6292), an Fc-engineered anti-CD25 , are in ongoing clinical trials to boost anti-tumor immunity by preserving IL-2 signaling on effector cells while depleting Tregs. Low-dose cyclophosphamide (CY) exploits the heightened sensitivity of Tregs to this alkylating agent, achieving selective depletion at doses that spare effector T cells. Administered orally or intravenously at 25-50 mg daily, low-dose CY induces apoptosis in CD4+CD25+Foxp3+ Tregs through mechanisms including aldehyde dehydrogenase inhibition and ATP release, leading to transient reductions of 30-50% in circulating and tumor-infiltrating Tregs within 1-2 weeks. In patients with malignant pleural mesothelioma, low-dose CY combined with immunotherapy depleted both naive and activated Tregs, correlating with improved effector T cell proliferation. Preclinical studies in neuroblastoma and colorectal cancer models demonstrate that low-dose CY transiently eliminates tumor Tregs, enhancing anti-tumor T cell responses and synergizing with vaccines. Clinical applications in breast cancer have shown durable Treg reductions lasting 4-6 weeks, supporting its use in metronomic regimens to sustain anti-tumor immunity. Oncolytic viruses (OVs) can target immunosuppressive pathways involving Tregs, including adenosine-mediated suppression, by lysing tumor cells and releasing damage-associated molecular patterns that reprogram the . , generated via the CD39/CD73 axis, activates receptors on Tregs to amplify their suppressive function; OVs disrupt this by inducing immunogenic and reducing levels through . For instance, engineered herpes simplex viruses expressing immunomodulators counteract adenosine-driven Treg activity, enhancing effector T cell infiltration in solid tumors. In preclinical models, OVs combined with receptor antagonists further diminish Treg suppression, promoting systemic anti-tumor immunity. Combining Treg depletion with inhibitors (ICIs) has shown promise in , where Tregs limit PD-1/ and CTLA-4 blockade efficacy. Low-dose CY pretreatment before (anti-CTLA-4) in a phase II trial for metastatic patients achieved an objective response rate of 25%, with reduced Treg frequencies correlating to prolonged . Anti-CD25 therapies like vopikitug are being evaluated with PD-1 inhibitors, showing enhanced + T cell activation in early trials. Oncolytic viruses such as (T-VEC) combined with in advanced yielded a 62% objective response rate in phase II studies, with 3-year overall survival of 54.8% in ICI-refractory patients as of 2024 data. RP1 (an oncolytic HSV) plus nivolumab in anti-PD-1-failed reported a 33% response rate and 75% one-year survival in 2025 phase II results, attributing benefits to reduced intratumoral Tregs and increased effector responses. These combinations underscore the potential of Treg depletion to overcome resistance in up to 2025.

Modulation in Autoimmunity

Regulatory T cells (Tregs) play a pivotal role in suppressing aberrant immune responses in autoimmune diseases, where their dysfunction or deficiency contributes to chronic inflammation and tissue damage. Modulation strategies aim to enhance Treg numbers, stability, or suppressive function through pharmacological, environmental, or personalized interventions, thereby restoring without broad . These approaches target induced Tregs (iTregs) differentiation, indirect functional boosting, and influences, with emerging evidence from clinical trials supporting their efficacy in conditions like (RA), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Vitamin D and all-trans retinoic acid (ATRA) are key modulators that promote iTreg differentiation from naïve + T cells, particularly in the presence of transforming growth factor-β (TGF-β). The active form of , 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), binds to the on T cells, upregulating expression and enhancing Treg suppressive capacity while inhibiting pro-inflammatory Th17 cells, which has shown protective effects in experimental models of . Similarly, ATRA, a derivative, synergizes with TGF-β to induce + iTregs by promoting activity and epigenetic modifications at the locus, thereby stabilizing the Treg phenotype and suppressing autoimmune responses in preclinical studies of and . These metabolites are produced by dendritic cells in the , highlighting their role in induction relevant to autoimmune . Anti-tumor necrosis factor (TNF) therapies, such as and , indirectly enhance Treg function in by alleviating TNF-mediated suppression of Treg expansion and activity. In patients, elevated TNF inhibits phosphorylation and Treg suppressive function via TNFRII signaling; anti-TNF agents reverse this by increasing the Treg/effector T cell ratio and promoting a distinct population of antigen-experienced Tregs that express higher levels of CTLA-4 and GITR, leading to improved clinical outcomes in phase II/III trials. This modulation occurs through enhanced IL-2 signaling and reduced , rather than direct Treg expansion, and correlates with decreased disease activity scores in responders. Microbiome-based interventions, including fecal microbiota transplantation (FMT), restore Treg induction by reshaping gut dysbiosis-associated immune imbalances in autoimmune diseases. In models of and SLE, FMT from healthy donors increases short-chain fatty acid-producing , which upregulate TGF-β and IL-10 signaling to promote colonic iTreg differentiation and expression, attenuating Th17-driven inflammation. Clinical case series in RA and SLE patients demonstrate that FMT reduces levels and disease activity, with sustained Treg enrichment observed up to 12 months post-treatment, suggesting potential as an adjunct therapy to conventional immunosuppressants. Recent trials up to 2025 emphasize biomarker-guided personalization to optimize Treg modulation in SLE and MS, focusing on low-dose interleukin-2 (IL-2) therapy. In SLE, baseline Treg expression and STAT5 levels predict response to low-dose IL-2, with phase II trials showing selective Treg expansion (up to 2-fold increase) and complete remission in 50% of biomarker-positive patients, guiding dose adjustments for enhanced efficacy. For MS, post-alemtuzumab low-dose IL-2 trials use MRI lesion burden and Treg:Th17 ratios as biomarkers, achieving stable disease progression and Treg activation without effector T cell overexpansion in phase I/II studies completed in 2024. These approaches enable stratified patient selection, minimizing non-responders and advancing precision immunomodulation.

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