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

Key Words:APC,antigen-presenting cell-CFSE,carboxyfluorescein succinimidylester-FACS,fluorescence-activated cell sorter-HBSS,Hanks'balanced salt solution-H-E,hematoxylin-eosin-IL,interleukin-IPEX,immune dysregulation, polyendocrinopathy,enteropathy,and X-linked inheritance-MAB,monoclonal antibody-nTreg,naturally occurring Foxp3+CD4+ regulatory T-cells-pancLN,pancreatic lymph node-Teff cell,effector T-cell ,tumor necrosis factor-a

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 cellsin 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.

Mreover,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 delines 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 altetations in nTreg cell function promote immune dysregulation and the onset of spointaneous autoimmunity.