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

Abstract

OBJECTIVE—In this study, we asked whether a possible quantitative or qualitative deficiency in naturally occurring Foxp3+CD4+ regulatory T-cells (nTreg), 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+ nTreg 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+ nTreg 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+ nTreg cells on the development of autoimmune diabetes, and we demonstrate that nTreg 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+ nTreg 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 nTreg 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 nTreg cells in NOD mice regulate diabetogenesis, but temporal alterations in nTreg cell function promote immune dysregulation and the onset of spontaneous autoimmunity.