▪ Abstract Naturally occurring CD4⁺regulatory T cells, the majority of which express CD25, are engaged in dominant control of self-reactive T cells, contributing to the maintenance of immunologic self-tolerance. Their depletion or functional alteration leads to the development of autoimmune disease in otherwise normal animals. The majority, if not all, of such CD25⁺CD4⁺regulatory T cells are produced by the normal thymus as a functionally distinct and mature subpopulation of T cells. Their repertoire of antigen specificities is as broad as that of naive T cells, and they are capable of recognizing both self and nonself antigens, thus enabling them to control various immune responses. In addition to antigen recognition, signals through various accessory molecules and via cytokines control their activation, expansion, and survival, and tune their suppressive activity. Furthermore, the generation of CD25⁺CD4⁺regulatory T cells in the immune system is at least in part developmentally and genetically controlled. Genetic defects that primarily affect their development or function can indeed be a primary cause of autoimmune and other inflammatory disorders in humans. Based on recent advances in our understanding of the cellular and molecular basis of this T cell–mediated immune regulation, this review discusses how naturally arising CD25⁺CD4⁺regulatory T cells contribute to the maintenance of immunologic self-tolerance and negative control of various immune responses, and how they can be exploited to prevent and treat autoimmune disease, allergy, cancer, and chronic infection, or establish donor-specific transplantation tolerance.

Naturally occurring Foxp3 ⁺ CD4 ⁺ regulatory T cells (Tregs) are essential for maintaining immunological self-tolerance and immune homeostasis. Here, we show that a specific deficiency of cytotoxic T lymphocyte antigen 4 (CTLA-4) in Tregs results in spontaneous development of systemic lymphoproliferation, fatal T cell–mediated autoimmune disease, and hyperproduction of immunoglobulin E in mice, and it also produces potent tumor immunity. Treg-specific CTLA-4 deficiency impairs in vivo and in vitro suppressive function of Tregs—in particular, Treg-mediated down-regulation of CD80 and CD86 expression on dendritic cells. Thus, natural Tregs may critically require CTLA-4 to suppress immune responses by affecting the potency of antigen-presenting cells to activate other T cells.

This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25⁺CD4⁺ T cells, which constitute 5–10% of peripheral CD4⁺ T cells. When the CD25⁺CD4⁺ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25⁺CD4⁺ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25⁺CD4⁺ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25⁺CD4⁺ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.