{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:09:14Z","timestamp":1791403754878,"version":"4.3.3"},"reference-count":25,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01-AI146202 , R01-DK081166"],"award-info":[{"award-number":["R01-AI146202 , R01-DK081166"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Type 1 Diabetes (T1D) is an organ-specific autoimmune disease in which T cells are major drivers, leading to the destruction of beta-cells and insulin deficiency. Although the B-chain of insulin is a critical target for islet-reactive CD4 T cells, the native sequence is poorly antigenic and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , insulin elicits only a weak Th1 response. We previously reported that post-translational modification of proinsulin through hybrid insulin peptide (HIP) formation leads to the synthesis of potent epitopes for islet-reactive CD4 T cells, and that cathepsin D (catD), a protease present in beta-cells, can mediate the formation of HIPs through a transpeptidation process. In the present study, we defined the specificity of catD for the insulin B-chain and show a high specificity for proteolytic cleavage following the disease-critical tyrosine 16 residue. We therefore hypothesized that HIP formation occurs at this amino acid. We designed a panel of HIPs containing insB\n                    <jats:sub>9\u201316<\/jats:sub>\n                    fragments linked to different secretory granule proteins and challenged splenocytes isolated from diabetic NOD mice with insB\n                    <jats:sub>9\u201316<\/jats:sub>\n                    HIPs; ELISPOT analysis showed elevated inflammatory responses to several peptides. Among this panel of HIPs, we identified the 2.40HIP, a fusion peptide between insB\n                    <jats:sub>9\u201316<\/jats:sub>\n                    and the C-peptide, as a potent epitope recognized by PD12-2.40, a diabetogenic CD4 T cell clone isolated from the islets of a 12-week-old NOD mouse. These results define a new antigenic region of the insulin B:9\u201323 peptide and demonstrate that this sequence of the B-chain becomes dramatically more antigenic when post-translationally modified through HIP formation.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1837267","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T09:50:32Z","timestamp":1785318632000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A novel region of the insulin B9\u201323 sequence is targeted by a HIP-reactive diabetogenic T cell clone"],"prefix":"10.3389","volume":"17","author":[{"given":"Janet M.","family":"Wenzlau","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlin","family":"Mangold","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelli","family":"Nicholson","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mylinh","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita C.","family":"Hohenstein","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]},{"name":"Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly S.","family":"Douglas","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James E.","family":"DiLisio","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Powell","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Delong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Haskins","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocky L.","family":"Baker","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United 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