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Studies of T1D in both patients and the nonobese diabetic (NOD) mouse model of the disease illustrate that beta cell\u2013specific CD8+ T cells are central contributors to the beta cell destruction characterizing the disease. Compared to HLA-A and HLA-B, relatively little is known about the participation of HLA-C\u2013restricted T cells in T1D. To tackle this question, we developed and characterized an NOD-based model of spontaneous T1D that transgenically expresses HLA-C*03:04, a common and enriched allotype in T1D patients. Using an unbiased screen of an exhaustive peptide library comprised of 8- to 11-mer peptides derived from the key autoantigen insulin, islet-infiltrating T cells from the mice were found to recognize the insulin A-chain peptides A11-19 and A13-21 presented by HLA-C*03:04. Guided by these findings, T-cell lines were established from the islets of HLA-C*03:04-positive human donors with T1D, including a donor with demise at onset of T1D. These human islet-derived T cells also responded to the conserved A11-19 and A13-21 peptides. The presence of HLA-C*03:04-restricted insulin-specific T cells in both mouse and human islets suggests the participation of peptides presented by HLA-C molecules in T1D pathogenesis. This work also demonstrates the utility of the mouse model in identifying human disease\u2013relevant HLA-C\u2013restricted epitopes and suggests a general strategy for the exploration and manipulation of HLA-C\u2013restricted T cells in autoimmune diseases.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf381","type":"journal-article","created":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T17:14:20Z","timestamp":1772385260000},"source":"Crossref","is-referenced-by-count":1,"title":["Islet-derived T cells from both mice and humans recognize conserved insulin A-chain peptides presented by HLA-C*03:04"],"prefix":"10.1093","volume":"215","author":[{"given":"Nitin","family":"Amdare","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riyasat","family":"Ali","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Manganaro","sequence":"additional","affiliation":[{"name":"Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School , Worcester, MA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason C","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]},{"name":"Division of Endocrinology and Diabetes, Department of Medicine, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Antal","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]},{"name":"Department of Pediatric Endocrinology, Children\u2019s Hospital at Montefiore , Bronx, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pere","family":"Santamaria","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary , Calgary, AB,","place":["Canada"]},{"name":"Institut D'Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS) , Barcelona,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally C","family":"Kent","sequence":"additional","affiliation":[{"name":"Diabetes Center of Excellence, Department of Medicine, University of Massachusetts Chan Medical School , Worcester, MA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-3598","authenticated-orcid":false,"given":"Teresa P","family":"DiLorenzo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]},{"name":"Division of Endocrinology and Diabetes, Department of Medicine, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]},{"name":"Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]},{"name":"The Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine , Bronx, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,1]]},"reference":[{"key":"2026051011263723500_vkaf381-B1","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/s41577-023-00985-4","article-title":"The immunology of type 1 diabetes","volume":"24","author":"Herold","year":"2024","journal-title":"Nat Rev Immunol"},{"key":"2026051011263723500_vkaf381-B2","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/S2213-8587(22)00218-2","article-title":"Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study","volume":"10","author":"Gregory","year":"2022","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2026051011263723500_vkaf381-B3","doi-asserted-by":"crossref","first-page":"6688","DOI":"10.1073\/pnas.1131954100","article-title":"Beta cell MHC class I is a late requirement for 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