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Proc Natl Acad Sci U S A. 2018 May 15;115(20):5265-5270. doi: 10.1073/pnas.1715590115. Epub 2018 Apr 30.

Revealing the specificity of regulatory T cells in murine autoimmune diabetes.

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Department of Surgery, University of California, San Francisco, CA 94143.
Diabetes Center, University of California, San Francisco, CA 94143.
Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305.
Geriatric Research Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304.
Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158.
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045.
Department of Surgery, University of California, San Francisco, CA 94143;


Regulatory T cells (Tregs) control organ-specific autoimmunity in a tissue antigen-specific manner, yet little is known about their specificity in a natural repertoire. In this study, we used the nonobese diabetic (NOD) mouse model of autoimmune diabetes to investigate the antigen specificity of Tregs present in the inflamed tissue, the islets of Langerhans. Compared with Tregs present in spleen and lymph node, Tregs in the islets showed evidence of antigen stimulation that correlated with higher proliferation and expression of activation markers CD103, ICOS, and TIGIT. T cell receptor (TCR) repertoire profiling demonstrated that islet Treg clonotypes are expanded in the islets, suggesting localized antigen-driven expansion in inflamed islets. To determine their specificity, we captured TCRαβ pairs from islet Tregs using single-cell TCR sequencing and found direct evidence that some of these TCRs were specific for islet-derived antigens including insulin B:9-23 and proinsulin. Consistently, insulin B:9-23 tetramers readily detected insulin-specific Tregs in the islets of NOD mice. Lastly, islet Tregs from prediabetic NOD mice were effective at preventing diabetes in Treg-deficient NOD.CD28-/- recipients. These results provide a glimpse into the specificities of Tregs in a natural repertoire that are crucial for opposing the progression of autoimmune diabetes.


T cell receptor; TCR sequencing; antigen specificity; regulatory T cells; type 1 diabetes

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