Islet-derived T cells from both mice and humans recognize conserved insulin A-chain peptides presented by HLA-C*03:04

Type 1 diabetes (T1D) is an autoimmune disease in which T cells mediate the elimination of the insulin-producing beta cells in the pancreatic islets, resulting in the need for exogenous insulin. Studies of T1D in both patients and the nonobese diabetic (NOD) mouse model of the disease illustrate that beta cell-specific 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-restricted 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-relevant HLA-C-restricted epitopes and suggests a general strategy for the exploration and manipulation of HLA-C-restricted T cells in autoimmune diseases.