Abstract

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.