regulatory t cell regulatory t cell 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. treg cells express the biomarkers cd4, foxp3, and cd25 and are thought to be derived from the same lineage as naïve cd4+ cells. 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. mouse models have suggested that modulation of treg cells can treat autoimmune disease and cancer and can facilitate organ transplantation and wound healing. 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. immunotherapy research is studying how regulation of t cells could possibly be utilized in the treatment of cancer. populations 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. another regulatory t cell subset is treg17 cells. regulatory t cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity. cd4+ foxp3+ cd25(high) regulatory t cells have been called "naturally occurring" regulatory t cells 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. development 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; 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. 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 there was observed, that some foxp3+ treg cells are recirculating back to thymus, where they have developed. this treg were mainly present in thymic medula, which is the main site of treg cells differentiation. the presence of this cells in thymus or addition into fetal thymic tissue culture suppress development of new treg cells by 34–60%, but tconv cells are not affected. that means, that recirculating treg to thymus inhibited just de novo development of treg cells. molecular mechanism of this process works due to the ability of treg to adsorb il-2 from the microenvironments, thus being able to induce apoptosis of other t cells which need il-2 as main growth factor. recirculating t reg cells in thymus express high amount of high affinity il-2 receptor α chain (cd25) encoded by il2ra gene which gather il-2 from thymic medulla, and decrease its concentration. new generated foxp3+ treg cells in thymus have not so high amount of il2ra expression. il-2 is a cytokine necessary for the development of treg cells in the thymus. it is important for t cells proliferation and survival, but in the case of its deficiency, il-15 may be replaced. however, treg cells' development is dependent on il-2. in humans, there was found population of cd31 negative treg cells in thymus. cd31 could be used as a marker of new generated treg cells as same as other t lymphocytes. mature and peripheral treg cells have decreased its expression. so it is possible that this regulatory mechanism of thymic treg cells development is also functional in humans. there is probably also positive regulation of thymic treg cells development caused by recirculating treg cells into thymus. there was found population of cd24 low foxp3+ in thymus with increased expression of il-1r2 (il1r2) compared with peripheral treg cells. high concentration of il-1β caused by inflammation decrease de novo development of treg cells in thymus. 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 they are helping to the development of de novo treg cells. high concentration of il-1β caused by inflammation decrease de novo development of treg cells in thymus. binding of il-1β to il1r2 on the surface of treg cells does not cause any signal transduction because there is no present intracellular (tir) toll interleukin-1 receptor domain, which is normally present in innate immune cells. function 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, interleukin 35, and interleukin 10. it also appears that regulatory t cells can induce other cell types to express interleukin-10. 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. reverse signalling through direct interaction with dendritic cells and the induction of immunosuppressive indoleamine 2,3-dioxygenase. signalling through the ectoenzymes cd39 and cd73 with the production of immunosuppressive adenosine. through direct interactions with dendritic cells by lag3 and by tigit. this review of treg interactions with dendritic cells provides distinction between mechanisms described for human cells versus mouse cells. 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. 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. 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. induced regulatory t cells 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". 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. the retinoic acid and tgf-beta produced by dendritic cells within this area signal for production of regulatory t cells. vitamin a and tgf-beta promote t cell differentiation into regulatory t cells opposed to th17 cells, even in the presence of il-6. the intestinal environment can lead to induced regulatory t cells with tgf-beta and retinoic acid, some of which express the lectin-like receptor cd161 and are specialized to maintain barrier integrity by accelerating wound healing. the tregs within the gut are differentiated from naïve t cells after antigen is introduced. it has recently been shown that human regulatory t cells can be induced from both naive and pre-committed th1 cells and th17 cells using a parasite-derived tgf-β mimic, secreted by heligmosomoides polygyrus and termed hp-tgm (h. polygyrus tgf-β mimic). hp-tgm can induce murine foxp3 expressing regulatory t cells that were stabile in presence of inflammation in vivo. 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