American Diabetes Association
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An Insulin-Chromogranin A Hybrid Peptide activates DR11 restricted T cells in human type 1 diabetes

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posted on 2024-01-31, 21:32 authored by Aïsha Callebaut, Perrin Guyer, Rocky L. Baker, Joylynn B. Gallegos, Anita C. Hohenstein, Peter A. Gottlieb, Chantal Mathieu, Lut Overbergh, Kathryn Haskins, Eddie A. James

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.


This work was supported by the National Institutes of Health (NIH) research grants R21 AI133059 (R.L.B.), R01 AI146202-01 (R.L.B.), and R01 DK081166 (K.H.) and a JDRF postdoctoral fellowship for A.C. (3-PDF-2023-1328-A-N).