Regulatory T cells and their role in rheumatic diseases: a potential target for novel therapeutic development

Tolerance to "self" is a major immune regulatory mechanism that protects the body's own tissues from immune-mediated damages and restricts active immune responses to those against microbial invaders (Figure 1). A classical type of tolerance, called central tolerance, is the mechanism by which "forbidden clones" of lymphocytes that recognize self antigens are eliminated in the thymus during normal lymphocyte development [1-3]. However, some lymphocyte clones with specificities for self antigens are found in animals and humans without autoimmunity [4-8]. In addition, autoimmunity can develop in the absence of defects in central tolerance. These findings initially led to the hypothesis that peripheral tolerancemust prevent auto-aggression by self-reactive T cells that escape thymic deletion. In the 1970s and 1980s, work on peripheral tolerance focused on characterization of specific suppressor T cells, the presumed regulators of immune responses in the periphery [9]. However, attempts to define and isolate suppressor T cells led to conflicting results, disappointment, and near abandonment of the field. With the development of new technologies in the 1990s, compelling evidence was put forward to support the existence of cellular subsets that possess immunosuppressive activities, this time under the name regulatory T cells[10].There are various types of regulatory T cells, including TCRαβ+CD4+, TCRαβ+CD8+, TCRαβ+CD4-CD8-, and TCRγι+ T cells. The majority of recent research has focused on TCRαβ+CD4+ regulatory T cells, of which there are several subtypes with distinct surface phenotypes, cytokine production profiles and mechanisms of immune suppression. Among the subtypes, T cells produced in the thymus and delivered to the periphery as a long-lived lineage of self-antigen-specific lymphocytes are called natural CD4+CD25high regulatory T cells (nTreg). In contrast+, CD4+ T cells that are recruited from circulating lymphocytes and acquire regulatory properties under partic