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The mechanisms underlying this functional bias remain elusive. Previous studies have reported that CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells from mice harboring dendritic cell (DC)-specific deletion of IL-27p28 display an increased capacity of IFN-\u03b3 production upon TCR stimulation. Here, we demonstrated that similarly altered functionality occurred in CD4SP thymocytes, recent thymic emigrants (RTEs), as well as naive T cells from either\n                    <jats:italic>\n                      Cd11c-p28\n                      <jats:sup>f\/f<\/jats:sup>\n                    <\/jats:italic>\n                    mice or mice deficient in the \u03b1 subunit of IL-27 receptor. Therefore, DC-derived IL-27p28-triggered, IL-27R\u03b1-mediated signal is critically involved in the establishment of functional bias against IFN-\u03b3 production during their development in the thymus. Epigenetic analyses indicated reduced DNA methylation of the\n                    <jats:italic>Ifng<\/jats:italic>\n                    locus and increased trimethylation of H3K4 at both\n                    <jats:italic>Ifng<\/jats:italic>\n                    and\n                    <jats:italic>Tbx21<\/jats:italic>\n                    loci in CD4SP thymocytes from\n                    <jats:italic>\n                      Cd11c-p28\n                      <jats:sup>f\/f<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Transcriptome profiling demonstrated that\n                    <jats:italic>Il27p28<\/jats:italic>\n                    ablation resulted in the coordinated up-regulation of STAT1-activated genes. Concurrently, STAT1 was found to be constitutively activated. Moreover, we observed increased accumulation of STAT1 at the\n                    <jats:italic>Ifng<\/jats:italic>\n                    and\n                    <jats:italic>Tbx21<\/jats:italic>\n                    loci and a strong correlation between STAT1 binding and H3K4me3 modification of these loci. Of note,\n                    <jats:italic>Il27p28<\/jats:italic>\n                    deficiency exacerbated the autoimmune phenotype of\n                    <jats:italic>\n                      Aire\n                      <jats:sup>-\/-<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Collectively, this study reveals a novel mechanism underlying the functional bias of newly generated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells and the potential relevance of such a bias in autoimmunity.\n                  <\/jats:p>","DOI":"10.7554\/elife.96868","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T07:25:23Z","timestamp":1714116323000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.96868","source":"Crossref","is-referenced-by-count":0,"title":["Thymic dendritic cell-derived IL-27p28 promotes the establishment of functional bias against IFN-\u03b3 production in newly generated CD4+ T cells through STAT1-related epigenetic mechanisms"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3338-8139","authenticated-orcid":true,"given":"Jie","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02v51f717","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, Peking University","place":["Beijing, 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