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These mutations are predominantly hypomorphic or dominant\u2010negative, reducing DNMT3A function. We tested whether\n Dnmt3a<\/jats:italic>\n mutations enhance the pathogenicity of autoreactive CD4\n +<\/jats:sup>\n T cells.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n Using the KRN\n +<\/jats:sup>\n TCR transgenic transfer model of autoimmune arthritis, in which autoreactive CD4\n +<\/jats:sup>\n T follicular helper (Tfh) cells drive disease, we assessed the impact of\n Dnmt3a<\/jats:italic>\n mutations introduced by CRISPR\u2010Cas9 or\n Cd4<\/jats:italic>\n cre<\/jats:sup>\n \u2010mediated recombination. Competitive bone marrow chimeras, immunization with sheep red blood cells, and autoreactive T cell transfer were used to evaluate Tfh responses, antibody production, and joint inflammation.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Loss of DNMT3A function in CD4\n +<\/jats:sup>\n T cells consistently reduced Tfh responses and IgG production during both immunization\u2010driven and autoreactive activation. In the KRN\n +<\/jats:sup>\n transfer model, mice receiving\n Dnmt3a<\/jats:italic>\n \u2010mutant autoreactive CD4\n +<\/jats:sup>\n T cells developed significantly attenuated joint inflammation, accompanied by reduced systemic interleukin\u20106 and autoantibody levels.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Wild\u2010type\n Dnmt3a<\/jats:italic>\n supports Tfh responses under both immunization\u2010driven and autoreactive conditions.\n Dnmt3a<\/jats:italic>\n loss\u2010of\u2010function in CD4\n +<\/jats:sup>\n T cells limits autoreactive inflammation, suggesting that clinical associations in RA may reflect effects in other hematopoietic lineages or T cell functions beyond Tfh\u2010dependent responses.\n <\/jats:p>\n \n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.70267","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T02:39:41Z","timestamp":1782787181000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Dnmt3a<\/i>\n Mutations Limit Normal and Autoreactive\n CD4<\/scp>\n +<\/sup>\n T Follicular Helper Responses and Attenuate T Cell\u2013Driven Joint Inflammation"],"prefix":"10.1002","author":[{"given":"Yunbing","family":"Shen","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine, Division of Rheumatology, Department of Medicine, Solna Karolinska Institutet and Karolinska University Hospital Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjaykumar","family":"Boddul","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Division of Rheumatology, Department of Medicine, Solna Karolinska Institutet and Karolinska University 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