Cell-intrinsic IL-7Rα deficiency in Foxp3+ Tregs increases type 1 diabetes incidence in NOD mice.

Abstract

Regulatory CD4+ T cells (Tregs), as defined by expression of the transcription factor Foxp3, strongly depend on the cytokine interleukin 2 (IL-2) for their survival and function and are often identified by the combination of high IL-2Rα (CD25) and low IL-7Rα (CD127) expression. Nevertheless, subsets expressing higher levels of IL-7Rα have been described, and IL-7 signaling does play a role in Treg function in some specific biologic contexts and tissues. The precise role of IL-7Rα-expressing Tregs in autoimmunity remains poorly defined though, potentially hampering current efforts to develop IL-7Rα blockade for the treatment of various autoimmune diseases. To ask whether cell-intrinsic IL-7Rα expression in Tregs was required for their function during type 1 diabetes (T1D) development, we generated non-obese diabetic (NOD) mice in which IL-7Rα is exclusively deleted in Foxp3-expressing Tregs. In young NOD mice, IL-7Rα deficiency did not alter Treg numbers and phenotype. However, 100% of NOD mice with IL-7Rα-deficient Tregs became diabetic, while the T1D incidence is typically around 50-60% in our colony. This increased susceptibility for T1D indicates that IL-7Rα expression in Tregs is required to protect a subset of NOD mice against islet autoimmunity. At the time of T1D onset, CD4+ and CD8+ T cells from NOD mice with IL-7Rα-deficient Tregs showed increased IFN-γ and IL-2 cytokine production. Our data demonstrate that cell-intrinsic IL-7R signaling in Foxp3+ Tregs is required to suppress effector T cell responses and to prevent full penetrance of T1D in NOD mice.