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In this study, we analyzed CD8 T cell receptor (TCR) clonotypes isolated from the pancreas of organ donors with and without T1D and assessed their reactivity to beta cells using stem cell-derived beta-like cells. We found that highly beta cell-reactive CD8 T cells were selectively present in the pancreas of T1D donors but were largely absent from donors without T1D. In contrast, virus-specific CD8 T cells were detected in pancreata of donors with and without T1D and showed no evidence of cross-reactivity to beta-like cells, indicating that pancreatic residency alone does not confer beta cell specificity. Among beta cell-reactive CD8 T cells in T1D, reactivity to native peptides from major islet proteins other than preproinsulin was rare. Thus, despite beta cell specificity as a hallmark of T1D, T cells reactive to native islet proteins other than preproinsulin do not infiltrate the islets. These results identify beta cell reactivity as a key functional feature separating T1D-associated CD8 T cells from other pancreatic T cells. This functional definition of pathogenic T cells offers a framework for understanding selective beta cell loss and for developing approaches to monitor and therapeutically target disease-relevant CD8 T cells.<\/jats:p>","DOI":"10.64898\/2026.06.08.729940","type":"posted-content","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T02:35:19Z","timestamp":1781145319000},"source":"Crossref","is-referenced-by-count":1,"title":["Beta cell reactivity defines disease-relevant pancreatic CD8 T cells in type 1 diabetes"],"prefix":"10.64898","author":[{"given":"Amanda M.","family":"Anderson","sequence":"first","affiliation":[{"name":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie G.","family":"Landry","sequence":"additional","affiliation":[{"name":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO, 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