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Because T\u2010cell receptor (TCR) signal quantity and quality can regulate T\u2010cell differentiation, citrullination within a T\u2010cell epitope has potential implications for T\u2010cell effector function. Here, we investigated how citrullination of an immunedominant T\u2010cell epitope affected Th17 development. Murine na\u00efve CD4<jats:sup>+<\/jats:sup> T\u00a0cells with a transgenic TCR recognising p89\u2010103 of the G1 domain of aggrecan (agg) were co\u2010cultured with syngeneic bone marrow\u2010derived dendritic cells (BMDC) presenting the native or citrullinated peptides. In the presence of pro\u2010Th17 cytokines, the peptide citrullinated on residue 93 (R93Cit) significantly enhanced Th17 development whilst impairing the Th2 response, compared to the native peptide. T\u00a0cells responding to R93Cit produced less IL\u20102, expressed lower levels of the IL\u20102 receptor subunit CD25, and showed reduced STAT5 phosphorylation, whilst STAT3 activation was unaltered. IL\u20102 blockade in native p89\u2010103\u2010primed T\u00a0cells enhanced the phosphorylated STAT3\/STAT5 ratio, and concomitantly enhanced Th17 development. Our data illustrate how a post\u2010translational modification of a TCR contact point may promote Th17 development by altering the balance between STAT5 and STAT3 activation in responding T\u00a0cells, and provide new insight into how protein citrullination may influence effector Th\u2010cell development in inflammatory disorders.<\/jats:p>","DOI":"10.1002\/eji.201546217","type":"journal-article","created":{"date-parts":[[2016,5,13]],"date-time":"2016-05-13T09:09:00Z","timestamp":1463130540000},"page":"1633-1643","source":"Crossref","is-referenced-by-count":8,"title":["Reduced TCR\u2010dependent activation through citrullination of a T\u2010cell epitope enhances Th17 development by disruption of the STAT3\/5 balance"],"prefix":"10.1002","volume":"46","author":[{"given":"Christopher","family":"Tibbitt","sequence":"first","affiliation":[{"name":"Musculoskeletal Research Group Institute of Cellular Medicine Newcastle University  U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"Falconer","sequence":"additional","affiliation":[{"name":"Rheumatology Research Group School of Immunity and Infection University of Birmingham  U.K."},{"name":"Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE)  U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"Stoop","sequence":"additional","affiliation":[{"name":"Department of Rheumatology Leiden University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem","family":"van Eden","sequence":"additional","affiliation":[{"name":"Institute of Infectious Diseases and Immunology Utrecht University  The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John H.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Musculoskeletal Research Group Institute of Cellular Medicine Newcastle University  U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catharien M.U.","family":"Hilkens","sequence":"additional","affiliation":[{"name":"Musculoskeletal Research Group Institute of Cellular Medicine Newcastle University  U.K."},{"name":"Arthritis Research UK Rheumatoid Arthritis Pathogenesis Centre of Excellence (RACE)  U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,7,12]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207577200"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni1254"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201242872"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.03.044"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2044"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1086\/422329"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900013"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-011110-130318"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri2094"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27622"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2015.53"},{"key":"e_1_2_7_13_1","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.4049\/jimmunol.136.7.2348","article-title":"Two types of murine helper T\u00a0cell clone. 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