Using a GFP reporter construct, Spence et al. demonstrate that Tregs within the inflamed islets of Langerhans in nonobese diabetic (NOD) mice are locally stimulated and activated by islet antigens via the TCR. Deep TCR sequencing showed clonal expansion and accumulation within the islets. Single cell paired αβTCR sequencing reveals that a significant portion of islet Tregs is insulin-specific, and an adoptive transfer of islet Tregs into NOD.C28-/- mice efficiently prevents diabetes development, pointing to the use of insulin-specific TCRs for engineered Treg therapy.
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 TCRalphabeta 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.
Author Info: (1) Department of Surgery, University of California, San Francisco, CA 94143. (2) Diabetes Center, University of California, San Francisco, CA 94143. (3) Department of Surgery, Uni
Author Info: (1) Department of Surgery, University of California, San Francisco, CA 94143. (2) Diabetes Center, University of California, San Francisco, CA 94143. (3) Department of Surgery, University of California, San Francisco, CA 94143. (4) Diabetes Center, University of California, San Francisco, CA 94143. (5) Department of Surgery, University of California, San Francisco, CA 94143. (6) 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. (7) Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158. (8) Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 80045. (9) 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. (10) Diabetes Center, University of California, San Francisco, CA 94143. (11) Diabetes Center, University of California, San Francisco, CA 94143. (12) Department of Surgery, University of California, San Francisco, CA 94143; qizhi.tang@ucsf.edu. Diabetes Center, University of California, San Francisco, CA 94143.
