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HIPs represent a unique posttranslational modification in autoimmunity and consist of peptide sequences from two beta\u2010cell proteins, one being proinsulin, covalently joined to form new nongenomic peptides. Using the nonobese diabetic (NOD) mouse model, we showed that HIPs are target antigens for a panel of diabetogenic CD4 T\u2010cell clones. The prototype clone of this panel is BDC\u20102.5, and the first HIP identified was the peptide ligand for BDC\u20102.5, the 2.5HIP, consisting of an insulin C\u2010peptide fragment combined with a natural cleavage product of chromogranin A. T cells with different TCRs, all specific for the 2.5HIP, were shown to be a dominant population among the T cells infiltrating the islets of NOD mice. T cells reactive to HIPs are significantly elevated in the PBMC of newly diagnosed patients with type 1 diabetes (T1D) and in at\u2010risk subjects, an important finding from a clinical standpoint. When coupled to biodegradable nanoparticles (NPs), HIPs can serve as epitopes to induce antigen\u2010specific tolerance. 2.5HIP NPs not only prevent transfer of disease by BDC\u20102.5\u2009T cells but also prolong islet graft survival in diabetic NOD mice. Investigation of the mechanisms underlying 2.5HIP NP\u2010induced tolerance revealed that protection occurs through an IL\u201010\u2010dependent process in which regulatory T cells in the graft tissue are increased, limiting dendritic cell licensing and the subsequent terminal differentiation of both CD4 and CD8 islet\u2010specific T cells.<\/jats:p>","DOI":"10.1111\/imr.70142","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T04:33:03Z","timestamp":1784781183000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hybrid Insulin Peptides as Antigens and Tolerogens for Pathogenic T Cells in Autoimmune Diabetes"],"prefix":"10.1111","volume":"341","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5430-6254","authenticated-orcid":false,"given":"Kathryn","family":"Haskins","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Delong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of Colorado School of Pharmacy  Aurora Colorado USA"}],"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  Aurora Colorado USA"}],"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  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0167\u20105699(92)90170\u2010C"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365\u20102567.2010.03362.x"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.37.10.1444"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065\u20102776(05)87004\u2010X"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2205920"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092\u20108674(93)90730\u2010e"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20051409"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.8.4730"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.5.1386"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.4.978"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.2337\/db07\u20101129"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830250430"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.20.8000"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.43.2.197"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1006\/jaut.2000.0377"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/345632a0"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.2337\/diab.40.7.842"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1844"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.2.908"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxf106"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad2791"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.2337\/db18\u20100200"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1416864111"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1716527115"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.926650"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20\u201002\u201000639.2000"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M600443\u2010MCP200"},{"key":"e_1_2_9_29_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2026.1837267","article-title":"A Novel Region of the Insulin B9\u201323 Sequence is Targeted by a HIP\u2010Reactive Diabetogenic T Cell Clone","volume":"17","author":"Wenzlau J. 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