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These MHCII molecules preferentially bind citrullinated peptides formed by posttranslational modification of arginine. Citrullinated peptide:HLA-DR complexes may act as arthritis-initiating neo-antigens for CD4+ T cells. Here, we used fluorophore-conjugated HLA-DR tetramers containing citrullinated peptides from human cartilage intermediate layer protein, fibrinogen, vimentin, or enolase 1 to track cognate CD4+ T cells. Immunization of HLA-DR transgenic mice with citrullinated peptides from vimentin or enolase 1 failed to cause any expansion of tetramer-binding cells, whereas immunization with citrullinated peptides from cartilage intermediate layer protein or fibrinogen elicited some expansion. The expanded tetramer-binding populations, however, had lower T helper 1 and higher regulatory T cell frequencies than populations elicited by viral peptides. These results indicate that HLA-DR\u2013bound citrullinated peptides are not neo-antigens and induce varying degrees of immune tolerance that could pose a barrier to rheumatoid arthritis.<\/jats:p>","DOI":"10.1084\/jem.20230209","type":"journal-article","created":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T02:21:08Z","timestamp":1696299668000},"update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["The CD4+ T cell repertoire specific for citrullinated peptides shows evidence of immune tolerance"],"prefix":"10.1084","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1659-6112","authenticated-orcid":true,"given":"Matthew K.","family":"McElwee","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology, University of Minnesota Medical School 1 , Minneapolis, MN, USA"},{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Minnesota Medical School 2 Division of Rheumatic and Autoimmune Diseases, Department of Medicine, , Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2810-6996","authenticated-orcid":true,"given":"Thamotharampillai","family":"Dileepan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology, University of Minnesota Medical School 1 , Minneapolis, MN, USA"},{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Minnesota Medical School 3 Department of Microbiology and Immunology, , Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5169-651X","authenticated-orcid":true,"given":"Shawn A.","family":"Mahmud","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology, University of Minnesota Medical School 1 , Minneapolis, MN, USA"},{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Minnesota Medical School 4 Division of Pediatric Rheumatology, Allergy and Immunology, Department of Pediatrics, , Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8009-7655","authenticated-orcid":true,"given":"Marc K.","family":"Jenkins","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Immunology, University of Minnesota Medical School 1 , Minneapolis, MN, USA"},{"id":[{"id":"https:\/\/ror.org\/017zqws13","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Minnesota Medical School 3 Department of Microbiology and Immunology, , Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"key":"2023101313455439400_bib1","doi-asserted-by":"publisher","first-page":"2255","DOI":"10.1016\/j.immuni.2022.11.009","article-title":"The pathogenesis of rheumatoid arthritis","volume":"55","author":"Alivernini","year":"2022","journal-title":"Immunity"},{"key":"2023101313455439400_bib2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0245541","article-title":"The role of posttranslational modifications in generating neo-epitopes that bind to rheumatoid arthritis-associated HLA-DR alleles and promote autoimmune T cell responses","volume":"16","author":"Becart","year":"2021","journal-title":"PLoS One"},{"key":"2023101313455439400_bib3","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/S1074-7613(00)80572-5","article-title":"Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes","volume":"8","author":"Crawford","year":"1998","journal-title":"Immunity"},{"key":"2023101313455439400_bib4","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1146\/annurev-immunol-031210-101400","article-title":"Follicular helper CD4 T cells (TFH)","volume":"29","author":"Crotty","year":"2011","journal-title":"Annu. 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