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 T1D.

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 T1D-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 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 (pancLN). 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 (T_eff). 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.

Conclusion: 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.