T regulatory cells

First discovered… The existence of T regulatory cells was first suggested by several animal models in the 1970s. Organ-specific autoimmunity was found to be induced in specific strains of mice that had been thymectomized 3 days after birth but not after thymectomy at 0 or 7 days. It was proposed that self-reactive T cells emerged from the thymus immediately after birth but that there existed a second, suppressive population of T cells that did not emerge until after day 3 of life. It was not until 1995, however, that the suppressive cells were characterized as those CD4+ T cells that co-expressed the IL2Rα chain, CD25. Direct evidence of their existence and in vitro suppressive function was then described in 1998.Do not confuse with... Suppressor T cells of the 1970s. Concurrent with the animal studies mentioned above, the literature also contained countless studies that described subpopulations of T cells with suppressive activity, which was attributed to soluble factors encoded by both immunoglobulin genes and the I–J locus of the major histocompatibility complex (MHC) region. But when an I–J locus was not found within the MHC and it was discovered that the genes encoding the T-cell receptor were distinct from the immunoglobulins, suppressor T cells quickly fell out of favor and suppressor T cells became a dirty term. Thus, in the current literature, CD4+CD25+ suppressor T cells are typically referred to as T regulatory cells (Tregs).Also do not confuse with... Conventional CD4+ T cells that express CD25 upon activation — expression of CD25 does not a Treg make... Once stimulated, effector CD4+ T cells express various surface markers associated with activation that are all also expressed on Tregs. Thus, activated effector CD4+ T cells are phenotypically similar to Tregs and can only be distinguished by a functional assay. A member of the forkhead family of transcription factors, FoxP3, was recently found to be specific to Tregs and is the best marker to date for distinguishing Tregs from effector T cells. However, the intracellular localization of FoxP3 limits its use as a tool to purify Tregs.What do they do? CD4+CD25+ T cells isolated from mice or humans are able to suppress the in vitro proliferative response of conventional CD4+ and CD8+ T cells. Evidence is also emerging that suggests Tregs can suppress the proliferation and function of other cell types, such as dendritic cells and B cells. Moreover, purified CD4+CD25+ T cells are able to suppress the induction of autoimmunity in numerous in vivo models of autoimmunity, including inflammatory bowel disease, gastritis and diabetes. Recent evidence suggests that Tregs do not prevent the activation or infiltration of autoreactive T cells, but they instead prevent effector functions such as the secretion of interferon γ.How do they do it? Although IL-10 secreted by CD4+CD25+ Tregs appears to play a protective role in some models of autoimmunity, the primary mechanism of suppression is dependent on cell contact and results in the inhibition of IL-2 transcription. Surprisingly and despite great effort, the molecules involved in this cell–cell contact remain elusive. Recent reports have suggested that cell-surface transforming growth factor (TGF) β, bound to Tregs, is responsible for their suppressive properties, but this theory has not generated widespread support. Other molecules such as lymphocyte activation gene 3 (LAG-3) and the negative costimulatory molecule CTLA-4 have also been implicated, but there is no agreement that they are responsible for the suppressive phenotype of Tregs.How are they regulated? The development of CD4+CD25+ Tregs is regulated by several pathways. Mice that are deficient in CD25, the IL-2β receptor CD122 and IL-2, all involved in IL-2 binding or signaling, either lack Tregs or have a severely reduced population. Mice that are deficient in CD28, an important co-stimulatory molecule, lack Tregs as well. Finally, mice that lack FoxP3 are also deficient in Tregs. However, only the ectopic expression of FoxP3 in CD4+CD25– T cells can confer the suppressive phenotype of Tregs, making it the key regulator of Treg development and function.Can we live without them? It appears that we cannot live for very long without Tregs. CD25- or CD122-deficient mice, which, as previously mentioned, lack Tregs, develop varying degrees of lymphoproliferation and autoimmunity, usually dying within 12 to 20 weeks of life. However, the adoptive transfer of purified CD4+CD25+ T cells during the neonatal period completely protects these animals. Mice that lack Foxp3 suffer from a fatal X-linked lymphoproliferative autoimmune syndrome and typically die at 3 weeks. These mice, too, can be completely protected by the transfer of purified CD4+CD25+ T cells. Also, humans with mutations in FOXP3 develop a syndrome called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) and, without bone marrow treatment, patients die early in life.