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1 diabetes (T1D) is an autoimmune disease characterized by T cell-mediated destruction of insulin-producing pancreatic beta cells. In both humans and the non-obese diabetic (NOD) mouse model of T1D, class II MHC alleles are the primary determinant of disease susceptibility. However, class I MHC genes also influence risk. These findings are consistent with the requirement for both CD4(+) and CD8(+) T cells in the pathogenesis of T1D. Although a large body of work has permitted the identification of multiple mechanisms to explain the diabetes-protective effect of particular class II MHC alleles, studies examining the protective influence of class I alleles are lacking. Here, we explored this question by performing biochemical and structural analyses of the murine class I MHC molecule H-2K(wm7), which exerts a diabetes-protective effect in NOD mice. We have found that H-2K(wm7) molecules are predominantly occupied by the single self-peptide VNDIFERI, derived from the ubiquitous protein histone H2B. This unexpected finding suggests that the inability of H-2K(wm7) to support T1D development could be due, at least in part, to the failure of peptides from critical beta-cell antigens to adequately compete for binding and be presented to T cells. Predominant presentation of a single peptide would also be expected to influence T-cell selection, potentially leading to a reduced ability to select a diabetogenic CD8(+) T-cell repertoire. The report that one of the predominant peptides bound by T1D-protective HLA-A*31 is histone derived suggests the potential translation of our findings to human diabetes-protective class I MHC molecules.","bibjson":{"author":[{"initials":"DR","lastname":"Brims","name":"Brims DR"},{"initials":"J","lastname":"Qian","name":"Qian J"},{"initials":"I","lastname":"Jarchum","name":"Jarchum I"},{"initials":"L","lastname":"Mikesh","name":"Mikesh L"},{"initials":"E","lastname":"Palmieri","name":"Palmieri E"},{"initials":"UA","lastname":"Ramagopal","name":"Ramagopal UA"},{"initials":"VN","lastname":"Malashkevich","name":"Malashkevich VN"},{"initials":"RJ","lastname":"Chaparro","name":"Chaparro RJ"},{"initials":"T","lastname":"Lund","name":"Lund T"},{"initials":"M","lastname":"Hattori","name":"Hattori M"},{"initials":"J","lastname":"Shabanowitz","name":"Shabanowitz J"},{"initials":"DF","lastname":"Hunt","name":"Hunt DF"},{"initials":"SG","lastname":"Nathenson","name":"Nathenson SG"},{"initials":"SC","lastname":"Almo","name":"Almo SC"},{"initials":"TP","lastname":"Dilorenzo","name":"Dilorenzo TP"}],"identifier":[{"id":"10.1093/intimm/dxp127","type":"doi"},{"id":"20093428","type":"pubmed"}],"issue":["3"],"journal":{"iso_abbreviation":"Int. Immunol.","name":""},"pages":["191-203"],"title":"Predominant occupation of the class I MHC molecule H-2Kwm7 with a single self-peptide suggests a mechanism for its diabetes-protective effect.","type":"article","url":"https://academic.oup.com/intimm/article-lookup/doi/10.1093/intimm/dxp127","volume":["22"],"year":[2010]},"in_pmc":"Y","in_pmce":"Y","open_access":"N"},"resolution":"2.50","same_as":{"pdbe":{"url":"https://www.ebi.ac.uk/pdbe/entry/pdb/3fol"},"rcsb":{"url":"https://www.rcsb.org/structure/3fol"}},"species":{"common_name":"Mouse","match_type":"histo:assign_species","scientific_name":"Mus musculus","slug":"mus_musculus"},"tcr":null,"title":"H2-Kwm7 binding \"VNDIFERI\" at 2.50Å resolution","unique_chain_count":3}}