Although interest in the concept of a lineage of T cells uniquely equipped to mediate suppressor function had largely been abandoned in the 1980s, the discovery by Sakaguchi et al in 1995 (1) that a subpopulation of CD4 T cells that coexpressed the interleukin-2 receptor (IL-2R) chain (CD25) played an important function in controlling the development of autoimmune disease in a mouse model rekindled interest in this controversial topic. The importance of CD4CD25 T cells in immunoregulation was further substantiated by in vitro studies that demonstrated that this subpopulation of T cells had a unique functional phenotype (2). They were nonresponsive to T cell receptor (TCR) stimulation and inhibited the responses of CD4CD25 T cells by an as yet uncharacterized cell contact–dependent, cytokine-independent mechanism. CD4CD25 T cells have now been shown to be involved in almost all aspects of immunoregulation, including the responses to autoantigens, alloantigens, tumor antigens, and pathogen-derived antigens, and even the maintenance of normal pregnancy. Studies in the past year have conclusively demonstrated that CD4CD25 T cells are the products of a unique lineage of T cells developing in the thymus (3). Both animals (scurfy mice) and humans (males with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) with mutations in the transcription factor Foxp3 do not develop CD4CD25 T cells in the thymus and succumb to autoimmune disease early in life. Transfection of Foxp3 into activated

CD4CD25 T cells converts these cells into functional suppressors (3). It has been hypothesized that CD4CD25 suppressors are generated during the course of T cell differentiation in the thymus, probably during the process of negative selection, where they display an intermediate-to-high–affinity TCR for the self class II major histocompatibility complex (MHC), but an affinity lower that that required for deletion. The expression of Foxp3 is induced during this stage of development, and the cells acquire their unique functional suppressor phenotype (Figure 1). Studies by multiple groups of investigators have shown that, in addition to the naturally occurring CD4CD25 T cell population, it is possible to generate in the periphery a distinct population of regulatory T cells that have been termed T regulatory cells type 1 (Tr1) or Th3 cells (4). In general, Tr1 cells are antigenspecific populations that are derived from conventional CD4CD25 naive precursors following exposure to antigen under conditions of limiting costimulation (Figure 1). Some of the factors that appear to direct the development of Tr1 cells include the suppressor cytokine IL-10, immunosuppressive drugs (eg, vitamin D3 and dexamethasone), immature dendritic cells, or coculture with naturally occurring CD4CD25 T cells. Tr1 cells may represent an important segment of the immune response to some pathogens that secrete products that induce IL-10 production, thereby promoting their development (5). The mechanism of suppression by Tr1 cells appears to be mediated by secretion of suppressor cytokines such as IL-10 and transforming growth factor (TGF). However, the difference in the mechanism of suppression between the induced Tr1 cells and the naturally occurring CD4CD25 cells may be more apparent than real. Thus, CD4CD25 T cells can mediate some of their suppressive effects in vivo by secreting IL-10, and a portion of the suppressive effects