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Hybrid Insulin Peptides are Recognized by Human T Cells in the Context of DRB1*04:01

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posted on 14.04.2020 by Ada Admin, David Arribas-Layton, Perrin Guyer, Thomas Delong, Mylinh Dang, I-Ting Chow, Cate Speake, Carla J. Greenbaum, William W. Kwok, Rocky L. Baker, Kathryn Haskins, Eddie A. James
T cells isolated from the pancreatic infiltrates of non-obese 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 utilizing 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 post-translational modification that may contribute to the loss of peripheral tolerance in T1D.

Funding

This work was supported by the National Institutes of Health (NIH) grant R01-DK-081166 (K.H.), R21AI133059 (R.L.B.), Juvenile Diabetes Research Foundation grant 2-SRA-2018-551-S-B (E.A.J), and the American Diabetes Association Pathway to stop Diabetes 1-15-ACE-14 (T.D.).

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