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

From the Department of Microbiology and Immunology and McGill Center for the Study of Host Resistance, McGill University, Montreal, Quebec, Canada

Address correspondence and reprint requests to Dr. Ciriaco A. Piccirillo, Department of Microbiology and Immunology, McGill University, 3775 University St., Room 510, Lyman Duff Medical Building, Montreal, QC, Canada H3A 2B4. E-mail: ciro.piccirillo{at}mcgill.ca

Key Words: APC, antigen-presenting cell • CFSE, carboxyfluorescein succinimidyl ester • 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 • nT_reg, naturally occurring Foxp3⁺CD4⁺ regulatory T-cells • pancLN, pancreatic lymph node • T_eff cell, effector T-cell • TNF-, tumor necrosis factor-

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.

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