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Regulatory T cells (also 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. The existence of a dedicated population of "suppressor" 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.
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 suggest that suppressive mechanism requires cell-to-cell contact with the cell being suppressed. However, 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 hypothesis’ 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 (TR or Treg). 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 specificly expressed on all Foxp3-expressing regulatory T cells. However, to date no such molecule has been identified.
CD4+CD25+ regulatory T cells have also been referred to as "naturally-occurring" regulatory T cells to distinguish them from "suppressor" T cell populations that are generated in vitro. In fact, the "naturally-occurring" CD4+CD25+ regulatory T cell population is a subset of the total Foxp3-expressing regulatory T cell population. The regulatory T cell field is further complicated by reports of additonal "suppressor" 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.
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 (see Online Mendelian Inheritance in Man IPEX). 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”.
Review Articles from the Scientific Literature
These two comprehensive reviews include valuable historical perspectives on experiments that have led to the current understanding of regulatory T cells.
- Shevach, Ethan M. (2002). "CD4+CD25+ suppressor T cells: more questions than answers." Nature Reviews Immunology 2, 389-400. PubMed Link Journal Link
- Sakaguchi, Shimon (2004). "Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses." Annual Review of Immunology 22, 531-562. PubMed Link Journal Link
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, Jason D., and Rudensky, Alexander. Y. (2005). "A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3." Nature Immunology 6, 331-337. PubMed Link Journal Link
- von Boehmer, Harald (2005). "Mechanisms of suppression by suppressor T cells." Nature Immunology 6, 338-344. PubMed Link Journal Link
- Sakaguchi, Shimon (2005). "Naturally arising Foxp3-expressing CD4+CD25+ regulatory T cells in immunological tolerance to self and non-self." Nature Immunology 6, 345-352. PubMed Link Journal Link
- Belkaid, Yasmine, and Rouse, Barry T. (2005). "Natural regulatory T cells in infectious disease." Nature Immunology 6, 353-360. PubMed Link Journal Link
External links
Entrez gene entries for human FOXP3 and mouse Foxp3 from the National Center for Biotechnology Information database. These entries contain a very large amount of the most current scientific information including nomenclature, map location within the genome, gene products and their attributes, markers, phenotypes, as well as links to citations, sequences, variation details, maps, expression, homologs, protein domains and external databases. It is updated as new information becomes available.
Additional information on the IPEX syndrome can be found at the GeneTests web site, a publicly funded medical genetics information resource. IPEX
"Regulatory T cell"