IL-7R signaling in regulatory T cells maintains peripheral and allograft tolerance in mice

Foxp3(+) CD4(+) regulatory T cells (T-reg) have a crucial role in controlling CD4(+) T-cell activation, proliferation, and effector function. However, the molecular mechanisms regulating T-reg function remain poorly understood. Here we assessed the role of IL-7, a key cytokine regulating T-cell homeostasis, in suppressor capacity of T-reg. Using a skin allograft model in which transplant acceptance is controlled by the number of transferred T-reg, we find that T-reg impair the proliferation of allogeneic CD4(+) T cells, decrease production of IFN gamma by effector T cells, and prevent early and increase late IL-7 induction by lymph node stromal cells. Increased IL-7 availability enhanced T-reg survival, stabilized T-reg molecular signature, enhanced surface IL-2R alpha expression, and improved IL-2 binding of T-reg, which diminished proliferation of alloreactive CD4(+) T cells. Sequestration of IL-7 or impairment of IL-7R signaling after allograft transplantation abolished T-reg-mediated tolerance by limiting their suppressive capacity. Aged Il7r alpha-Delta T-reg mice displayed mild symptoms of autoimmunity correlating with impaired expansion of effector T-reg in response to IL-2. Thus, IL-7R signaling on T-reg supports the functional activity of effector T-reg by increasing their IL-2 sensitivity in the lymph node during peripheral and allograft tolerance.