Hybrid insulin peptides (HIPs) formed through covalent cross-linking of proinsulin fragments to secretory granule peptides are detectable within murine and human islets. The 2.5HIP (C-peptide-Chromogranin A (CgA) HIP), recognized by the diabetogenic BDC-2.5 clone, is a major autoantigen in the NOD mouse. However, the relevance of this epitope in human disease is currently unclear. A recent study probed T-cell reactivity toward HIPs in patients with type 1 diabetes, documenting responses in one third of the subjects and isolating several HIP-reactive T-cell clones. In this study, we isolated a novel T cell clone and showed that it responds vigorously to the human equivalent of the 2.5HIP. Although the responding subject carried the risk-associated DRB1*04:01/DQ8 haplotype, the response was restricted by DRB1*11:03 (DR11). HLA class II tetramer staining revealed higher frequencies of HIP9-reactive T cells in individuals with diabetes than in controls. Furthermore, in DR11+ subjects carrying the DRB4 allele, HIP9-reactive T-cell frequencies were higher than observed frequencies for the immunodominant proinsulin 9-28 epitope. Finally, there was a negative correlation between HIP9-reactive T-cell frequency and age at diagnosis. These results provide direct evidence that this C-peptide-CgA HIP is relevant in human type 1 diabetes and suggest a mechanism by which non-risk HLA haplotypes may contribute to the development of β-cell autoimmunity.

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