IntroductionImmunologic self-tolerance is critical for the prevention of autoimmunity and maintenance of immune homeostasis. The ability of the immune system to discriminate between self and nonself is controlled by central and peripheral tolerance mechanisms. The former involves deletion of self-reactive T cells in the thymus at an early stage of development, 1,2 whereas peripheral tolerance involves several mechanisms, including T-cell anergy and ignorance. Since these mechanisms are not completely effective and potentially autoantigen-reactive lymphocytes escape into the periphery, additional mechanisms are involved in the maintenance of self-tolerance. A number of subsets of regulatory T cells play an important role in preventing activation of autoantigenreactive T cells. Among these are naturally occurring "professional" regulatory T cells (Tregs). In this regard, studies carried out during the past decade provided strong evidence for the existence of a unique CD4 ϩ CD25 ϩ population of naturally occurring regulatory/suppressor T cells that actively prevent both the activation and the effector function of autoreactive T cells that have escaped other mechanisms of tolerance. [3][4][5] Removal of this population from normal rodents leads to the spontaneous development of various autoimmune diseases, organ specific as well as systemic. Notably, the generation of CD4 ϩ CD25 ϩ T-regulatory cells in the immune system is developmentally and genetically controlled, as recent studies have demonstrated that the transcription factor, FoxP3, is essential for their thymic development 6 and is sufficient to activate a program of suppressor function in peripheral CD4 ϩ CD25 Ϫ T cells. 7 Genetic defects that affect the development or function of CD4 ϩ CD25 ϩ Tregs can be a primary cause of autoimmune and other inflammatory disorders in humans. 8 It has been proposed that during the initiation of an adaptive immune response, dendritic cells can induce effector CD4 ϩ T cells to become resistant to the suppressive effects of Tregs by secreting IL-6, thus allowing a productive immune response to take place. 9 Similarly, glucocorticoid-induced tumor necrosis factor-like receptor (GITR) engagement on effector T cells by its ligand (GITRL) expressed on antigen-presenting cells (APCs) has been claimed to render them resistant to suppression by CD4 ϩ CD25 ϩ Tregs, 10 and may also have an effect on the function of Tregs. 11 Recent studies have revealed the presence of CD4 ϩ CD25 ϩ Tregs in human peripheral blood, where they constitute up to 5% of the CD4 ϩ T cells. 12,13 These cells are similar to those described in the mouse in that they require cell-to-cell contact to exert their suppressive effect. Whether a soluble factor is involved depends on the experimental system used. 14,15 Tumor necrosis factor (TNF) is a pleiotropic cytokine critical for cell trafficking, inflammation, maintenance of secondary lymphoid organ structure, and host defense against various pathogens. 16 Because of this panoply of effects, TNF plays a critic...

IntroductionThe development and differentiation of immune cells is carefully orchestrated by an array of cytokines. Signal transducers and activators of transcription (Stats) represent a small but critical family of transcription factors that play important roles in transmitting cytokine signals. Consequently, Stats are critical for immunoregulation and the development of immune cells. 1,2 Stat5a and Stat5b are two closely related proteins that have overlapping functions with respect to lymphoid development and differentiation. 3,4 Gene targeting of Stat5a and Stat5b (collectively referred to as Stat5), results in impairment in the development of T, B, and natural killer (NK) cells. [5][6][7] In mice in which the amino termini of Stat5a and Stat5b are deleted (denoted as Stat5 ⌬N mice), major disruption of various immune cell parameters was noted. 8,9 However, residual Stat5 function permits T cell development, albeit suboptimally. 10 This contrasts with the complete absence of Stat5a/b, which results in dramatic reduction in thymocyte numbers, in part due to effects on lymphoid stem cell function. 5 T regulatory (Treg) cells comprise a population of cells enriched in CD4 ϩ CD25 ϩ T cells that suppresses T-cell proliferation and function and attenuates immune responses against self-or nonself-antigens. [11][12][13] Naturally arising Treg cells are produced in the thymus as a functionally distinct T-cell subpopulation, whereas adaptive Treg cells are induced from naive T cells after antigen exposure in the periphery. [14][15][16][17] In classic studies, mice develop organ-specific autoimmune disease following neonatal thymectomy, which is corrected by reconstitution with CD4 ϩ CD25 ϩ T cells. 13 The essential role of Treg cells in maintaining tolerance has been confirmed by findings that defective function of this subset is a feature of many models of autoimmunity. 18 More recently, it was discovered independently by several groups that a subset of CD4 ϩ CD25 ϩ T cells expresses the transcription factor Foxp3, which is necessary and sufficient for Treg cell development and function. [19][20][21][22] Foxp3 is highly conserved in mice and humans. Mutation of Foxp3 in mice (scurfy) results in early autoimmune disease, 23 whereas mutations of human Foxp3 are associated with a disorder known as immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). 24 In mice, Foxp3 is a reliable marker for the Treg lineage.Multiple lines of evidence have indicated that IL-2 is an important growth factor for Treg development and maintenance. Mice lacking IL-2 or its receptor subunits, IL-2R␣ (CD25) and IL-2R␤ (CD122), have deficits in CD4 ϩ CD25 ϩ Treg cells and develop autoimmune disease similar to Foxp3 Ϫ/Ϫ mice. [25][26][27] However, IL-2 is dispensable for Treg cell development, as some Foxp3-expressing cells are present in Il2 Ϫ/Ϫ and Il2ra Ϫ/Ϫ mice, suggesting the involvement of other cytokines. 28 In vitro culture of CD4 ϩ T cells with transforming growth factor-␤1 (TGF-␤1) can promote the generation o...

Nonactivated CD4+CD25+ regulatory T cells constitutively express glucocorticoid-induced TNFR family-related receptor (GITR), a TNFR family member whose engagement was presumed to abrogate regulatory T cell-mediated suppression. Using GITR−/− mice, we report that GITR engagement on CD25−, not CD25+ T cells abrogates T cell-mediated suppression. Mouse APCs constitutively express GITR ligand (GITR-L), which is down-regulated following TLR signaling in vivo. Although GITR−/−CD25− T cells were capable of mounting proliferative responses, they were incapable of proliferation in the presence of physiological numbers of CD25+ T cells. Thus, GITR-L provides an important signal for CD25− T cells, rendering them resistant to CD25+-mediated regulation at the initiation of the immune response. The down-regulation of GITR-L by inflammatory stimuli may enhance the susceptibility of effector T cells to suppressor activity during the course of an infectious insult.