Hybrid Insulin Peptides Are Recognized by Human T Cells in the Context of DRB104:01

• Published in: Diabetes (New York, N.Y.) Vol. 69; no. 7; pp. 1492 - 1502
• Main Authors: Arribas-Layton, David, Guyer, Perrin, Delong, Thomas, Dang, Mylinh, Chow, I-Ting, Speake, Cate, Greenbaum, Carla J., Kwok, William W., Baker, Rocky L., Haskins, Kathryn, James, Eddie A.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2020
• Subjects: CD4-Positive T-Lymphocytes - immunology; Cross Reactions; Cytokines; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - immunology; Drb1 protein; Epitopes; HLA-DRB1 Chains - immunology; Humans; Immunological memory; Immunological tolerance; Immunology and Transplantation; Insulin; Insulin - chemistry; Insulin - immunology; Insulin-Secreting Cells - immunology; Lymphocytes; Lymphocytes T; Mass spectroscopy; Organ donors; Pancreas; Peptide Fragments - chemistry; Peptide Fragments - immunology; Peptides; Peripheral blood; Phenotypes; T-Lymphocytes - immunology
• DOI: 10.2337/db19-0620
• ISSN: 0012-1797; 1939-327X

T cells isolated from the pancreatic infiltrates of nonobese diabetic mice have been shown to recognize epitopes formed by the covalent cross-linking of proinsulin and secretory granule peptides. Formation of such hybrid insulin peptides (HIPs) was confirmed through mass spectrometry, and responses to HIPs were observed among the islet-infiltrating T cells of pancreatic organ donors and in the peripheral blood of individuals with type 1 diabetes (T1D). However, questions remain about the prevalence of HIP-specific T cells in humans, the sequences they recognize, and their role in disease. We identified six novel HIPs that are recognized in the context of DRB1*04:01, discovered by using a library of theoretical HIP sequences derived from insulin fragments covalently linked to one another or to fragments of secretory granule proteins or other islet-derived proteins. We demonstrate that T cells that recognize these HIPs are detectable in the peripheral blood of subjects with T1D and exhibit an effector memory phenotype. HIP-reactive T-cell clones produced Th1-associated cytokines and proliferated in response to human islet preparations. These results support the relevance of HIPs in human disease, further establishing a novel posttranslational modification that may contribute to the loss of peripheral tolerance in T1D.