Regulatory T cell

The regulatory T cells (Tregs pronunciation: /ˈtiːrɛɡ/), formerly known as suppressor T cells, are a subpopulation of T cells which modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells.[1] Tregs 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, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis.[3]

Mouse models have suggested that modulation of Tregs can treat autoimmune disease and cancer and can facilitate organ transplantation.[4] Their implications for cancer are complicated. Tregs 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 Tregs in the tumor microenvironment is indicative of a poor prognosis, and Tregs are thought to suppress tumor immunity, thus hindering the body's innate ability to control the growth of cancerous cells.[5] Recent immunotherapy research is studying how regulation of T cells could possibly be utilized in the treatment of cancer.[6]

Regulatory T 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 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 "Tregs" are different from helper T cells.[7] Another regulatory T cell subset is Treg17 cells.[8] Regulatory T cells are involved in shutting down immune responses after they have successfully eliminated invading organisms, and also in preventing autoimmunity.[9]

CD4+ Foxp3+ 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.[10]

Development

All T cells come from progenitor cells from 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 haemopoietically-derived MHC class II-expressing cells in the medulla or Hassal’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; 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.

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).

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.

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.[11]

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".[12] 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.

Regulatory T cells and disease

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 (the most well-known of which is HIV), mycobacterial infections (like tuberculosis), and various parasitic infections including Leishmania and malaria.

Studies of human subjects with a history of leishmania infection suggest that modulation of CD8+ suppressor T cells is, at least partly, mediated by cytokines. Leishmania specific CD4+ helper T cells predominate in adults with strong protective immunity (skin-test positive with no history of clinical infection). When added to autologous leishmania infected macrophages these T cells cause parasite death and secretion of large amounts of interferon-gamma and lymphotoxin. CD8+ T suppressor cells predominate in patients with no protective immunity (visceral leishmaniasis patients). When added to autologous peripheral blood mononuclear cells isolated after successful treatment, these T cells inhibit interferon-gamma secretion and proliferation and increase interleukin-6 and interleukin-10 secretion. A soluble factor(s) generated by antigen or phytohemagglutinin stimulation of leishmania-specific CD4+ helper T cells from skin-test positive adults killed CD8+ T cells but not CD4+ helper T cells when added to culture media. Soluble factors generated by antigen stimulation of peripheral blood mononuclear cells from skin-test positive adults prevented CD8+ suppressor T cell mediated increases in interleukin-10 secretion. These findings suggest that antigen stimulation of CD4+ helper T cells results in production of cytokines that kill or down regulate CD8+ T suppressor cells. Once the leishmania infection has been eliminated and leishmania antigens are gone, CD8+ T suppressor cells down-regulate CD4+ T helper cells. Isolation of cytokines that inhibit and kill CD8+ T suppressor cells might be useful in treating diseases that involve immune suppression such as leishmaniasis, AIDS, and certain cancers.[13][14]

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.[15]

CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25− T cells.[16]

A recent study shows that cerebral ischemia can increase bone marrow CD4(+)CD25(+)Foxp3(+) regulatory T cells via signals from the sympathetic nervous system.[17]

Regulatory T cells and cancer

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 be found in the tumor microenvironment.[18] Although it is not entirely understood, it is thought that these lymphocytes target cancerous cells and therefore slow or terminate the development of the tumor. However, this process is complicated because Tregs seem to be preferentially trafficked to the tumor microenvironment. While Tregs normally make up only about 4% of CD4+ T Cells, they can make up as much as 20-30% of the total CD4+ population around the tumor microenvironment.[19]

Although high levels of TILs were initially thought to be important in determining an immune response against cancer, it is now widely recognized that the ratio of Tregs to Teffectors in the tumor microenvironment is a determining factor in the success of the immune response against the cancer. High levels of Tregs in the tumor microenvironment are associated with[6] poor prognosis in many cancers, such as ovarian, breast, renal, and pancreatic cancer.[19] This indicates that Tregs suppress Teffector 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 Tregs 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's ability to suppress general inflammation which is known to trigger cell proliferation and metastasis .[19] These opposite effects indicate that Treg's 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 Tregs are preferentially trafficked to the tumor microenvironment, the chemotaxis is probably driven by the production of chemokines by the tumor. Treg infiltration into the tumor microenvironment is facilitated by the binding of the chemokine receptor CCR4, which is expressed on Tregs, to its ligand CCL22, which is secreted by many types of tumor cells.[20] Treg expansion at the cite of the tumor could also explain the increased levels of Tregs. The cytokine, TGF-β, which is commonly produced by tumor cells, is known to induce the differentiation and expansion of Tregs.[20]

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

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's fate.[21] 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.[22] 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, some research groups use another marker, the absence or low-level expression of the surface protein CD127 in combination with the presence of CD4 and CD25. 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.

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.[23] Interplay between the Th17 cells and regulatory T cells are important in many diseases like respiratory diseases.[24]

Recent evidence suggests that mast cells may be important mediators of Treg-dependent peripheral tolerance.[25]

Regulatory T cell epitopes

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.[26][27][27][28]

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.[29][30][31][32][33][34][35][36][37]

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.[38][39]

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”.

References

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  33. ↑ (PDF). Journal of Clinical Immunology http://www.epivax.com/wp-content/uploads/2013/02/Tregitope-Clinical-Immunology-2012.pdf. Retrieved July 2013. Check date values in: |access-date= (help); Missing or empty |title= (help)
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  35. ↑ (PDF). World Journal of Gastroenterology http://www.epivax.com/wp-content/uploads/2013/02/Adeno-associated-virus-mediated-delivery-of-Tregitope-167-2012.pdf. Retrieved July 2013. Check date values in: |access-date= (help); Missing or empty |title= (help)
  36. ↑ (PDF). Neurology Research International http://www.epivax.com/wp-content/uploads/2013/02/Tregitopes_MS_DeGroot_2011.pdf. Retrieved July 2013. Check date values in: |access-date= (help); Missing or empty |title= (help)
  37. ↑ (PDF). Blood Journal http://www.epivax.com/wp-content/uploads/2013/02/DeGroot_Tregitope_Blood_2008.pdf. Retrieved July 2013. Check date values in: |access-date= (help); Missing or empty |title= (help)
  38. ↑ Online Mendelian Inheritance in Man IPEX
  39. ↑ ipex at NIH/UW GeneTests
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