[HTML][HTML] Regulatory T cells: key controllers of immunologic self-tolerance

S Sakaguchi - Cell, 2000 - cell.com
Cell, 2000cell.com
Our immune system protects us from a myriad of potentially pathogenic microorganisms
while avoiding reacting with constituents of our body; ie, we are tolerant of “self.” Failure of
immunologic self-tolerance often leads to the development of autoimmune disease, which is
estimated to afflict up to 5% of the population. Although the etiology of autoimmune disease
is at present largely unknown, it is well documented that T cells are the key mediators of
many autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM) …
Our immune system protects us from a myriad of potentially pathogenic microorganisms while avoiding reacting with constituents of our body; ie, we are tolerant of “self.” Failure of immunologic self-tolerance often leads to the development of autoimmune disease, which is estimated to afflict up to 5% of the population. Although the etiology of autoimmune disease is at present largely unknown, it is well documented that T cells are the key mediators of many autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM), autoimmune thyroiditis, and autoimmune gastritis accompanying pernicious anemia. Furthermore, there is mounting evidence that normal healthy individuals harbor potentially pathogenic self-reactive T cells. For example, immunization of normal animals with a self-antigen in potent adjuvant can induce dormant self-reactive T cells to attack the antigen, eliciting inflammatory tissue damage. Self-reactive T cell clones can also easily be isolated from the peripheral blood of normal healthy individuals by repeated in vitro stimulation with self-molecules. Moreover, many tumor-associated antigens recognized by autologous T cells in cancer patients have now turned out to be normal self-constituents, not abnormal products of mutated genes, indicating that tumor immunity is in part an autoimmunity. One of the current key issues in immunology is therefore to elucidate how potentially hazardous (or sometimes beneficial) self-reactive T cells are generated in physiological or disease states, and how they are regulated to avoid autoimmune disease (or not to attack autologous tumor cells). A better understanding of the mechanisms underlying immunologic tolerance will lead to better treatments for autoimmune disease, cancer, and transplant rejection.
During T cell maturation in the thymus, immature T cells express an enormously diverse range of T cell antigen receptors (TCRs) formed by random rearrangements of TCR α and β chain gene segments, but only T cells expressing TCRs that recognize major histocompatibility complex (MHC) and associated self-peptides with moderate affinity can differentiate (positive selection). T cells whose TCRs fail to bind the MHC/self-peptide complex and T cells expressing TCRs that bind the complex too strongly are subjected to programmed cell death (death by neglect and negative selection, respectively). However, thymic negative selection does not seem to be sufficient to control self-reactive T cells and thereby prevent autoimmune disease. Self-reactive T cells that have somehow escaped thymic negative selection are further subjected to control in the periphery; T cells can be rendered anergic (ie, functionally inactivated without death) or deleted upon encounter with self-antigens in the periphery. In addition to these “passive” mechanisms of controlling self-reactive T cells, there appears to be a “dominant” control mechanism—certain T cells actively downregulate the activation/proliferation of self-reactive T cells. The existence of such regulatory (or suppressor) T cells has been a great controversy among immunologists and has been given little credibility for many years, largely because of the paucity of reliable markers for defining the cell, the ambiguity in the molecular basis of suppressive phenomena, and even the elusive nature of some suppressive phenomena themselves. Nevertheless, if one asks which mechanism of self-tolerance should, when it goes awry, directly lead to autoimmune disease or which one, when strengthened, can prevent autoimmune disease, accumulating experimental evidence now suggests that removal or inactivation of a certain regulatory T cell population can break …
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