Mechanisms And Dynamics Of Regulatory T Cell Function

Abstract

Regulatory T (Treg) cells, a subset of CD4+ T cells whose development and function is specified by the transcription factor Foxp3, are essential for maintenance of immune homeostasis at steady state as well as during inflammatory and infections conditions. Congenital deficiency of Treg cells in mice and humans as well as inducible ablation of Treg cells in adult mice results in rapid and lethal spontaneous T-cell driven autoimmunity. The mechanisms by which Treg cells function, however, remain relatively unknown. Here, we have attempted to elucidate some of these mechanisms and to provide a framework for understanding how suppressor function may be divided amongst distinct subpopulations of Treg cells. We demonstrate that—in addition to its essential role in Treg cell differentiation in the thymus—T cell receptor (TCR) expression in Treg cells is required for the Treg cell transition from a naïve to an effector state that occurs in the periphery and for continuous maintenance of suppressor function. We further show—as a proof of principal—through generation of mice harboring a monoclonal population of Treg cells that TCR-dependent Treg cell function can be uncoupled to some extent from antigenic specificity and repertoire diversity. Lastly, we explore how antigen-experienced effector Treg cells that have undergone an additional differentiation marked by stable expression of high amounts of the transcription factor T-bet selectively suppress TH1 autoimmunity and participate in TH1 responses to pathogenic challenge. Together, these studies provide insight into how Treg cell function is elaborated and organized for optimal maintenance of immune tolerance.