{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:47:38Z","timestamp":1790610458864,"version":"4.1.0"},"reference-count":40,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2018,8,22]],"date-time":"2018-08-22T00:00:00Z","timestamp":1534896000000},"content-version":"vor","delay-in-days":48,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/100000041","name":"American Diabetes Association","doi-asserted-by":"publisher","award":["1-14-BS-089"],"award-info":[{"award-number":["1-14-BS-089"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000041","name":"ADA","doi-asserted-by":"publisher","award":["1-15-JF-04"],"award-info":[{"award-number":["1-15-JF-04"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000041","name":"ADA","doi-asserted-by":"publisher","award":["1-15-ACE-14"],"award-info":[{"award-number":["1-15-ACE-14"]}],"id":[{"id":"10.13039\/100000041","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008664","name":"JDRF","doi-asserted-by":"publisher","award":["2-2012-197"],"award-info":[{"award-number":["2-2012-197"]}],"id":[{"id":"10.13039\/100008664","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21-AI-133059"],"award-info":[{"award-number":["R21-AI-133059"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-DK-081166"],"award-info":[{"award-number":["R01-DK-081166"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-DK-111733"],"award-info":[{"award-number":["R01-DK-111733"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-DK-099317"],"award-info":[{"award-number":["R01-DK-099317"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,9,1]]},"abstract":"<jats:p>We recently established that hybrid insulin peptides (HIPs), formed in islet \u03b2-cells by fusion of insulin C-peptide fragments to peptides of chromogranin A or islet amyloid polypeptide, are ligands for diabetogenic CD4 T-cell clones. The goal of this study was to investigate whether HIP-reactive T cells were indicative of ongoing autoimmunity. MHC class II tetramers were used to investigate the presence, phenotype, and function of HIP-reactive and insulin-reactive T cells in NOD mice. Insulin-reactive T cells encounter their antigen early in disease, but they express FoxP3 and therefore may contribute to immune regulation. In contrast, HIP-reactive T cells are proinflammatory and highly diabetogenic in an adoptive transfer model. Because the frequency of antigen-experienced HIP-reactive T cells increases over progression of disease, they may serve as biomarkers of autoimmune diabetes.<\/jats:p>","DOI":"10.2337\/db18-0200","type":"journal-article","created":{"date-parts":[[2018,7,5]],"date-time":"2018-07-05T14:16:55Z","timestamp":1530800215000},"page":"1836-1846","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":72,"title":["CD4 T Cells Reactive to Hybrid Insulin Peptides Are Indicators of Disease Activity in the NOD Mouse"],"prefix":"10.2337","volume":"67","author":[{"given":"Rocky L.","family":"Baker","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine at Denver, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Braxton L.","family":"Jamison","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine at Denver, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy A.","family":"Wiles","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine at Denver, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin S.","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, National Jewish Health, Denver, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gene","family":"Barbour","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine at Denver, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda","family":"Bradley","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine at Denver, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Delong","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine at Denver, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel S.","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research, National Jewish Health, Denver, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine at Denver, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5430-6254","authenticated-orcid":false,"given":"Kathryn","family":"Haskins","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine at Denver, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2018,7,5]]},"reference":[{"key":"2022031210314313400_B1","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.2337\/diab.37.10.1444","article-title":"T-lymphocyte clone specific for pancreatic islet antigen","volume":"37","author":"Haskins","year":"1988","journal-title":"Diabetes"},{"key":"2022031210314313400_B2","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1126\/science.2205920","article-title":"Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone","volume":"249","author":"Haskins","year":"1990","journal-title":"Science"},{"key":"2022031210314313400_B3","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/ni.1844","article-title":"Chromogranin A is an autoantigen in type 1 diabetes","volume":"11","author":"Stadinski","year":"2010","journal-title":"Nat Immunol"},{"key":"2022031210314313400_B4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.4049\/jimmunol.1501190","article-title":"Cutting edge: nonobese diabetic mice deficient in chromogranin a are protected from autoimmune diabetes","volume":"196","author":"Baker","year":"2016","journal-title":"J Immunol"},{"key":"2022031210314313400_B5","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.jaut.2013.10.003","article-title":"Chromogranin A is a T cell antigen in human type 1 diabetes","volume":"50","author":"Gottlieb","year":"2014","journal-title":"J Autoimmun"},{"key":"2022031210314313400_B6","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1126\/science.aad2791","article-title":"Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion","volume":"351","author":"Delong","year":"2016","journal-title":"Science"},{"key":"2022031210314313400_B7","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.jaut.2016.10.007","article-title":"An insulin-IAPP hybrid peptide is an endogenous antigen for CD4 T cells in the non-obese diabetic mouse","volume":"78","author":"Wiles","year":"2017","journal-title":"J Autoimmun"},{"key":"2022031210314313400_B8","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1038\/nm.4203","article-title":"Analysis of self-antigen specificity of islet-infiltrating T cells from human donors with type 1 diabetes","volume":"22","author":"Babon","year":"2016","journal-title":"Nat Med"},{"key":"2022031210314313400_B9","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1002\/eji.1830250430","article-title":"Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice","volume":"25","author":"Daniel","year":"1995","journal-title":"Eur J Immunol"},{"key":"2022031210314313400_B10","doi-asserted-by":"crossref","first-page":"16729","DOI":"10.1073\/pnas.1113954108","article-title":"Specificity and detection of insulin-reactive CD4+ T cells in type 1 diabetes in the nonobese diabetic (NOD) mouse","volume":"108","author":"Crawford","year":"2011","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031210314313400_B11","doi-asserted-by":"crossref","first-page":"4913","DOI":"10.4049\/jimmunol.1301927","article-title":"Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice","volume":"191","author":"Pauken","year":"2013","journal-title":"J Immunol"},{"key":"2022031210314313400_B12","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nature03523","article-title":"Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice","volume":"435","author":"Nakayama","year":"2005","journal-title":"Nature"},{"key":"2022031210314313400_B13","doi-asserted-by":"crossref","first-page":"3990","DOI":"10.4049\/jimmunol.1301480","article-title":"Cutting edge: CD4 T cells reactive to an islet amyloid polypeptide peptide accumulate in the pancreas and contribute to disease pathogenesis in nonobese diabetic mice","volume":"191","author":"Baker","year":"2013","journal-title":"J Immunol"},{"key":"2022031210314313400_B14","doi-asserted-by":"crossref","first-page":"4429","DOI":"10.1073\/pnas.1502967112","article-title":"Regulatory vs. inflammatory cytokine T-cell responses to mutated insulin peptides in healthy and type 1 diabetic subjects","volume":"112","author":"Nakayama","year":"2015","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031210314313400_B15","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1084\/jem.189.2.331","article-title":"Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes","volume":"189","author":"H\u00f6glund","year":"1999","journal-title":"J Exp Med"},{"key":"2022031210314313400_B16","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1084\/jem.20011353","article-title":"Pancreatic lymph nodes are required for priming of beta cell reactive T cells in NOD mice","volume":"196","author":"Gagnerault","year":"2002","journal-title":"J Exp Med"},{"key":"2022031210314313400_B17","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/ni.1739","article-title":"Intraclonal competition limits the fate determination of regulatory T cells in the thymus","volume":"10","author":"Bautista","year":"2009","journal-title":"Nat Immunol"},{"key":"2022031210314313400_B18","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S1074-7613(00)00080-7","article-title":"Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion","volume":"13","author":"Bouneaud","year":"2000","journal-title":"Immunity"},{"key":"2022031210314313400_B19","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/ni1227","article-title":"Initial T cell frequency dictates memory CD8+ T cell lineage commitment","volume":"6","author":"Marzo","year":"2005","journal-title":"Nat Immunol"},{"key":"2022031210314313400_B20","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1002\/eji.200425891","article-title":"Kinetics of costimulatory molecule expression by T cells and dendritic cells during the induction of tolerance versus immunity in vivo","volume":"35","author":"Hochweller","year":"2005","journal-title":"Eur J Immunol"},{"key":"2022031210314313400_B21","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1126\/science.1160062","article-title":"CTLA-4 control over Foxp3+ regulatory T cell function","volume":"322","author":"Wing","year":"2008","journal-title":"Science"},{"key":"2022031210314313400_B22","doi-asserted-by":"crossref","first-page":"4285","DOI":"10.4049\/jimmunol.172.7.4285","article-title":"Immune regulation by self-reactive T cells is antigen specific","volume":"172","author":"Tanchot","year":"2004","journal-title":"J Immunol"},{"key":"2022031210314313400_B23","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1084\/jem.20041033","article-title":"Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node","volume":"202","author":"Samy","year":"2005","journal-title":"J Exp Med"},{"key":"2022031210314313400_B24","doi-asserted-by":"crossref","first-page":"4516","DOI":"10.4049\/jimmunol.181.7.4516","article-title":"Regulatory T cells prevent transfer of type 1 diabetes in NOD mice only when their antigen is present in vivo","volume":"181","author":"Tonkin","year":"2008","journal-title":"J Immunol"},{"key":"2022031210314313400_B25","doi-asserted-by":"crossref","first-page":"7738","DOI":"10.4049\/jimmunol.175.11.7738","article-title":"Effector function of diabetogenic CD4 Th1 T cell clones: a central role for TNF-alpha","volume":"175","author":"Cantor","year":"2005","journal-title":"J Immunol"},{"key":"2022031210314313400_B26","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1084\/jem.20022125","article-title":"The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice","volume":"198","author":"Ansari","year":"2003","journal-title":"J Exp Med"},{"key":"2022031210314313400_B27","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1084\/jem.20061577","article-title":"Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway","volume":"203","author":"Fife","year":"2006","journal-title":"J Exp Med"},{"key":"2022031210314313400_B28","doi-asserted-by":"crossref","first-page":"e55","DOI":"10.2337\/dc14-2349","article-title":"Precipitation of autoimmune diabetes with anti-PD-1 immunotherapy","volume":"38","author":"Hughes","year":"2015","journal-title":"Diabetes Care"},{"key":"2022031210314313400_B29","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1111\/jdi.12531","article-title":"Fulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy","volume":"7","author":"Okamoto","year":"2016","journal-title":"J Diabetes Investig"},{"key":"2022031210314313400_B30","doi-asserted-by":"crossref","first-page":"529","DOI":"10.2337\/db13-1737","article-title":"PD-L1-driven tolerance protects neurogenin3-induced islet neogenesis to reverse established type 1 diabetes in NOD mice","volume":"64","author":"Li","year":"2015","journal-title":"Diabetes"},{"key":"2022031210314313400_B31","doi-asserted-by":"crossref","first-page":"8000","DOI":"10.1073\/pnas.86.20.8000","article-title":"Pancreatic islet-specific T-cell clones from nonobese diabetic mice","volume":"86","author":"Haskins","year":"1989","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031210314313400_B32","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/0092-8674(93)90730-E","article-title":"Following a diabetogenic T cell from genesis through pathogenesis","volume":"74","author":"Katz","year":"1993","journal-title":"Cell"},{"key":"2022031210314313400_B33","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.immuni.2009.07.008","article-title":"T cell islet accumulation in type 1 diabetes is a tightly regulated, cell-autonomous event","volume":"31","author":"Lennon","year":"2009","journal-title":"Immunity"},{"key":"2022031210314313400_B34","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.2337\/db07-1129","article-title":"On the pathogenicity of autoantigen-specific T-cell receptors","volume":"57","author":"Burton","year":"2008","journal-title":"Diabetes"},{"key":"2022031210314313400_B35","doi-asserted-by":"crossref","first-page":"571","DOI":"10.4049\/jimmunol.1400043","article-title":"TCR affinity and tolerance mechanisms converge to shape T cell diabetogenic potential","volume":"193","author":"Bettini","year":"2014","journal-title":"J Immunol"},{"key":"2022031210314313400_B36","doi-asserted-by":"crossref","first-page":"5265","DOI":"10.1073\/pnas.1715590115","article-title":"Revealing the specificity of regulatory T cells in murine autoimmune diabetes","volume":"115","author":"Spence","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031210314313400_B37","doi-asserted-by":"crossref","first-page":"97322","DOI":"10.1172\/jci.insight.97322","article-title":"High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity","volume":"3","author":"Sprouse","year":"2018","journal-title":"JCI Insight"},{"key":"2022031210314313400_B38","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/nature16962","article-title":"Expanding antigen-specific regulatory networks to treat autoimmunity","volume":"530","author":"Clemente-Casares","year":"2016","journal-title":"Nature"},{"key":"2022031210314313400_B39","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1900\/RDS.2012.9.319","article-title":"Tolerance strategies employing antigen-coupled apoptotic cells and carboxylated PLG nanoparticles for the treatment of type 1 diabetes","volume":"9","author":"Prasad","year":"2012","journal-title":"Rev Diabet Stud"},{"key":"2022031210314313400_B40","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.jaut.2017.12.010","article-title":"Tolerogenic Ag-PLG nanoparticles induce tregs to suppress activated diabetogenic CD4 and CD8 T cells","volume":"89","author":"Prasad","year":"2018","journal-title":"J Autoimmun"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db18-0200","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/67\/9\/1836\/537924\/db180200.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/67\/9\/1836\/537924\/db180200.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:35:57Z","timestamp":1667406957000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/67\/9\/1836\/15937\/CD4-T-Cells-Reactive-to-Hybrid-Insulin-Peptides"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,7,5]]},"references-count":40,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2018,7,5]]},"published-print":{"date-parts":[[2018,9,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db18-0200","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,7,5]]}}}