Regulatory T cell

Regulatory T cells (also known as suppressor T cells) are a specialized subpopulation of T cells that act to suppress or attenuate immune activation and maintain immune system homeostasis. 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 has firmly established their existence and the critical role these cells play 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 targeted to potentiate cancer immunotherapy.

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) which 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 CD25 (interleukin-2 receptor alpha chain). The first convincing evidence for the existence of a dedicated regulatory T cell population used these two cell surface molecules (CD4 and CD25) to define the population and thus these cells are commonly 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 undermined by expression of CD25 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. However, the regulatory T cell population as more accurately defined by Foxp3 expression extends beyond the CD4⁺CD25⁺ operational definition and is not complicated by expression of Foxp3 on activated T cells. Increased amounts 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.

The clearest evidence that regulatory T cells play a critical role in immune system function comes from genetic mutations in Foxp3 which have been identified in both humans and mice. Humans with mutations in Foxp3 suffer from a severe and rapidly fatal autoimmune disorder known as Immunoproliferation, Polyendcrinopathy, Enteropathy X-linked (IPEX) syndrome (see Online Mendelian Inheritance in Man IPEX). An analogous disease is also observed in a spontaneous Foxp3 mutant mouse known as “scurfy”. Evidence is now accumulating that regulatory T cell activity is amplified in a variety of infectious contexts, mediating suppression during retroviral and bacterial infections including immunity to Leishmania and malaria parasites in mouse models. There is also some suggestion that the pathogens themselves can manipulate the regulatory cells to immunosuppress the host and so potentiate their own survival. The molecular mechanism by which regulatory T cells exert their suppressor/regulatory activity has not been definitively characterized. However it is believed to require cell-to-cell contact with the cell being suppressd. The immunosuppressive cytokines TGF-beta and interleukin-10 (IL-10) have also been implicated in regulatory T cell function.

Review Articles from the Scientific Literature

Shevach, E. M. (2002). CD4⁺CD25⁺ suppressor T cells: more questions than answers. Nature Reviews Immunology 2, 389-400. PubMed Link Journal Link

Sakaguchi, S. (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 researchers. A subscrition (either personal or university) may be required to access these articles.

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. Nat Immunol 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

jor overhall and addition of references from the scientific literature