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Regulatory T cell

Regulatory T cells (sometimes known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. The existence of a dedicated population of suppressive T cells was the subject of significant controversy among immunologists for many years. However, recent advances in the molecular characterization of this cell population have firmly established their existence and their critical role in the vertebrate immune system. Interest in regulatory T cells has been heightened by evidence from experimental mouse models demonstrating that the immunosuppressive potential of these cells can be harnessed therapeutically to treat autoimmune diseases and facilitate transplantation tolerance or specifically eliminated to potentiate cancer immunotherapy.

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T regulatory cell 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 so that responses do not go haywire. Regulatory T cells come in many flavors, including those that express the CD8 transmembrane glycoprotein (CD8+ T cells), those that express CD4, CD25 and Foxp3 (CD4+CD25+ regulatory T cells or "Tregs") and other T cell types that have suppressive function. These cells are involved in closing down immune responses after they have successfully tackled invading organisms and also in keeping in check immune responses that may potentially attack one's own tissues (autoimmunity).

CD4⁺Foxp3⁺ regulatory T cells have been referred to as "naturally-occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. The regulatory T cell field is further complicated by reports of additional suppressive T cell populations, including Tr1, CD8⁺CD28^-, and Qa-1 restricted T cells. However the contribution of these populations to self-tolerance and immune homeostasis is less well defined.

Development

The first evidence that the thymus is critical in the production of Treg cells were the initial experiments by Sakaguchi et al. Neonatal thymectomy at three days of age in mice results in autoimmunity, which provided the data which reignited interest in regulatory T cells. All T cells come from progenitor cells from the bone marrow which become committed to their linage in the thymus. All T cells begin as CD4-CD8-TCR- cells at the DN (double-negative) stage, where an individual cell will combine its T cell receptor genes to form a 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 haemopoetically-derived MHC class II expressing cells in the medulla or Hassal’s corpuscles in the thymus. It seems that 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. Treg do not have the limited TCR expression of NKT or γδ T cells; Treg have a larger TCR diversity than effector T cells, biased towards self-peptides.

The exact process of Treg selection is still unknown, but appears to be a process determined by the affinity of interaction with the self-peptide MHC complex. Selection to become a Treg is a “Goldilocks” process; T cell which receives very strong signals will undergo apoptotic death; a cell which 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 then 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 either in 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 development in the thymus, as thymic Treg from TGF-β insensitive TGFβRII-DN mice are functional.

Function

To function properly, the immune system must 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.

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 immunosuppressive cytokines TGF-beta and Interleukin 10 (IL-10) have also been implicated in regulatory T cell function.

An important question in the field of immunology 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. Current hypotheses suggest that 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 and various parasitic infections including Leishmania and malaria.

Molecular characterization

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 fate. The large majority of Foxp3-expressing regulatory T cells are found within the major histocompatibility complex (MHC) class II restricted CD4-expressing (CD4⁺) helper T cell 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.

Prior to the identification of Foxp3, expression of these two cell surface molecules (CD4 and CD25) was used to define the population and thus these cells are often referred to as CD4⁺CD25⁺ regulatory T cells (T_R or T_reg). However, the use of CD25 as a marker for regulatory T cells is problematic as CD25 is also expressed on non-regulatory T cells in settings of immune activation such as during an immune response to a pathogens. As defined by CD4 and CD25 expression, regulatory T cells comprise about 5-10% of the mature CD4⁺ helper T cell subpopulation in mice and about 1-2% CD4⁺ helper T cells in humans. Foxp3 is not expressed on activated T cells and the regulatory T cell population as more accurately defined by Foxp3 expression extends beyond the CD4⁺CD25⁺ operational definition. Typically, 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.

Recent evidence suggests that mast cells may be important mediators of Treg-dependent peripheral tolerance.^[1]

Genetic deficiency

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 suffer from a severe and rapidly fatal autoimmune disorder known as Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.^[2]^[3]

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 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”.

References

These two comprehensive reviews include valuable historical perspectives on experiments that have led to the current understanding of regulatory T cells.

Shevach EM (2002). "CD4+ CD25+ suppressor T cells: more questions than answers". Nat. Rev. Immunol. 2 (6): 389-400. doi:10.1038/nri821. PMID 12093005.
Sakaguchi S (2004). "Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses". Annu. Rev. Immunol. 22: 531-62. doi:10.1146/annurev.immunol.21.120601.141122. PMID 15032588.

The following group of review articles were published as part of a special "Focus on Regulatory T cells" issue of the journal Nature Immunology. The issue also includes a "Classics" section listing important primary literature from the field as recommended by a group of prominent immunologists. A subscription (either personal or university) may be required to access this content.

Fontenot JD, Rudensky AY (2005). "A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3". Nat. Immunol. 6 (4): 331-7. doi:10.1038/ni1179. PMID 15785758.
von Boehmer H (2005). "Mechanisms of suppression by suppressor T cells". Nat. Immunol. 6 (4): 338-44. doi:10.1038/ni1180. PMID 15785759.
Sakaguchi S (2005). "Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self". Nat. Immunol. 6 (4): 345-52. doi:10.1038/ni1178. PMID 15785760.
Belkaid Y, Rouse BT (2005). "Natural regulatory T cells in infectious disease". Nat. Immunol. 6 (4): 353-60. doi:10.1038/ni1181. PMID 15785761.