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- Title
An Insulin-Chromogranin A Hybrid Peptide Activates DR11-Restricted T Cells in Human Type 1 Diabetes.
- Authors
Callebaut, Aïsha; Guyer, Perrin; Baker, Rocky L.; Gallegos, Joylynn B.; Hohenstein, Anita C.; Gottlieb, Peter A.; Mathieu, Chantal; Overbergh, Lut; Haskins, Kathryn; James, Eddie A.
- Abstract
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 nonobese diabetic 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 patients 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 (designated HIP9). Although the responding patient 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 control participants. Furthermore, in DR11+ participants 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 nonrisk HLA haplotypes may contribute to the development of β-cell autoimmunity. Article Highlights: A hybrid insulin peptide formed from C-peptide–WE14 is a potent ligand for the diabetogenic BDC-2.5 clone, but its relevance in human disease is unclear. A human T-cell clone specific for the C-peptide–WE14 HIP is restricted by HLA-DRB1*11, a nonrisk allele. Using an HLA class II tetramer, we observed increased frequencies of HIP-reactive cells T cells in individuals with diabetes compared with control participants and an inverse correlation between frequency and age of onset. These results suggest a pathogenic role for the C-peptide–WE14 HIP and provide a plausible mechanism for the expansion of disease-driving T-cell responses in individuals with nonrisk HLA haplotypes.
- Subjects
TYPE 1 diabetes; T cells; PEPTIDES; HUMAN cloning; SECRETORY granules; HISTOCOMPATIBILITY antigens; T cell receptors
- Publication
Diabetes, 2024, Vol 73, Issue 5, p743
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db23-0622