Functional Waning of Naturally Occurring CD4+ Regulatory T-Cells Contributes to the Onset of Autoimmune Diabetes

OBJECTIVE: In this study, we asked whether a possible quantitative or qualitative deficiency in naturally occurring Foxp3(+)CD4(+) regulatory T-cells (nT(reg)), which display potent inhibitory effects on T-cell functions in vitro and in vivo, may predispose to the development of type 1 diabetes. RESEARCH DESIGN AND METHODS: We assessed the frequency and function of Foxp3(+) nT(reg) cells in primary and secondary lymphoid tissues in the NOD animal model of type 1 diabetes. RESULTS: We show that the cellular frequency of Foxp3(+) nT(reg) cells in primary and secondary lymphoid tissues is stable and does not decline relative to type 1 diabetes-resistant mice. We show that thymic and peripheral CD4(+)CD25(+) T-cells are fully functional in vivo. We also examined the functional impact of CD4(+)Foxp3(+) nT(reg) cells on the development of autoimmune diabetes, and we demonstrate that nT(reg) cells do not affect the initial priming or expansion of antigen-specific diabetogenic T-cells but impact their differentiation in pancreatic lymph nodes. Moreover, CD4(+)Foxp3(+) nT(reg) cells also regulate later events of diabetogenesis by preferentially localizing in the pancreatic environment where they suppress the accumulation and function of effector T-cells. Finally, we show that the nT(reg) cell functional potency and intra-pancreatic proliferative potential declines with age, in turn augmenting diabetogenic responses and disease susceptibility. CONCLUSIONS: This study demonstrates that Foxp3-expressing nT(reg) cells in NOD mice regulate diabetogenesis, but temporal alterations in nT(reg) cell function promote immune dysregulation and the onset of spontaneous autoimmunity.