Control of Foxp3+ regulatory T cell abundance and function by distinct signals in different immune environments

Abstract

Immune tolerance and activation depend on precise control over the number and function of immunosuppressive Foxp3+ regulatory T (Treg) cells. The importance of interleukin (IL)-2 in immune tolerance is demonstrated by the lethal autoimmunity that develops in animals deficient for IL-2 or its receptor; however, IL-2 is not required for Treg cell development, <italic>in vitro</italic> activity, or to maintain total Treg cell numbers. Thus, the precise mechanism by which IL-2 controls Treg cell homeostasis and immune tolerance remains unclear. Here we show that that IL-2 selectively maintains a population of quiescent CD44<super>lo</super>CD62L<super>hi</super> Treg cells that gain access to paracrine IL-2 produced in the T cell zones of secondary lymphoid tissues due to their expression of the chemokine receptor CCR7. By contrast, CD44<super>hi</super>CD62L<super>lo</super>CCR7<super>lo</super> Treg cells that populate non-lymphoid tissues do not respond to IL-2 <italic>in vivo</italic> and are insensitive to IL-2 blockade; instead, their maintenance depends on continued signaling through the co-stimulatory receptor ICOS. Thus, we define a fundamental homeostatic subdivision in Treg cells based on their localization and provide an integrated framework for understanding how Treg cell abundance and function are controlled by unique signals in different tissue environments.