Control of Regulatory T Cell Migration, Function, and Homeostasis

Abstract

Foxp3(+) regulatory T cells (Tregs) are essential for preventing autoimmunity and uncontrolled inflammation, and they modulate immune responses during infection and the development of cancer. Accomplishing these tasks requires the widespread distribution of Tregs in both lymphoid and nonlymphoid tissues, and the selective recruitment of Tregs to different tissue sites has emerged as a key checkpoint that controls tissue inflammation in autoimmunity, infection, and cancer development, as well as in the context of allograft acceptance or rejection. Additionally, Tregs are functionally diverse, and it has become clear that some of this diversity segregates with Treg localization to particular tissue sites. In this article, I review the progress in understanding the mechanisms of Treg trafficking and discuss factors controlling their homeostatic maintenance and function in distinct tissue sites.

Figure 1

Model for inflammatory and non-inflammatory functions of IL-2. Weak activation of CD4⁺ effector T cells in non-inflammatory environments results in low-level ‘non-synaptic’ IL-2 secretion that promotes Treg cell function and blunts the response (Top). During strong activation in inflammatory conditions, this early inhibition is overcome, resulting in cell proliferation and formation of T-T synapses that facilitate paracrine IL-2 signaling between effector T cells and exclude Treg cells, promoting effector and memory T cell formation.