Beta cell reactivity defines disease-relevant pancreatic CD8 T cells in type 1 diabetes

Type 1 diabetes (T1D) is characterized by immune-mediated destruction of pancreatic beta cells, yet the properties that distinguish disease-associated CD8 T cells from other pancreatic resident T cells remain incompletely defined. 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.