{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T21:19:32Z","timestamp":1793827172817,"version":"4.6.1"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:00:00Z","timestamp":1687910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>T-bet-expressing Th17 (T-bet<jats:sup>+<\/jats:sup>ROR\u03b3t<jats:sup>+<\/jats:sup>) cells are associated with the induction of pathology during experimental autoimmune encephalomyelitis (EAE) and the encephalitic nature of these Th17 cells can be explained by their ability to produce GM-CSF. However, the upstream regulatory mechanisms that control <jats:italic>Csf2<\/jats:italic> (gene encoding GM-CSF) expression are still unclear. In this study, we found that Th17 cells dynamically expressed GATA3, the master transcription factor for Th2 cell differentiation, during their differentiation both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Early deletion of <jats:italic>Gata3<\/jats:italic> in three complimentary conditional knockout models by Cre-ERT2, <jats:italic>hCd2<\/jats:italic><jats:sup>Cre<\/jats:sup> and <jats:italic>Tbx21<\/jats:italic><jats:sup>Cre<\/jats:sup>, respectively, limited the pathogenicity of Th17 cells during EAE, which was correlated with a defect in generating pathogenic T-bet-expressing Th17 cells. These results indicate that early GATA3-dependent gene regulation is critically required to generate a <jats:italic>de novo<\/jats:italic> encephalitogenic Th17 response. Furthermore, a late deletion of <jats:italic>Gata3<\/jats:italic> via Cre-ERT2 in the adoptive transfer EAE model resulted in a cell intrinsic failure to induce EAE symptoms which was correlated with a substantial reduction in GM-CSF production without affecting the generation and\/or maintenance of T-bet-expressing Th17 cells. RNA-Seq analysis of <jats:italic>Gata3-<\/jats:italic>sufficient and <jats:italic>Gata3<\/jats:italic>-deficient CNS-infiltrating CD4<jats:sup>+<\/jats:sup> effector T cells from mixed congenic co-transfer recipient mice revealed an important, cell-intrinsic, function of GATA3 in regulating the expression of <jats:italic>Egr2<\/jats:italic>, <jats:italic>Bhlhe40<\/jats:italic>, and <jats:italic>Csf2<\/jats:italic>. Thus, our data highlights a novel role for GATA3 in promoting and maintaining the pathogenicity of T-bet-expressing Th17 cells in EAE, via putative regulation of Egr2, Bhlhe40, and GM-CSF expression.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1186580","type":"journal-article","created":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T10:06:47Z","timestamp":1687946807000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["GATA3 induces the pathogenicity of Th17 cells via regulating GM-CSF expression"],"prefix":"10.3389","volume":"14","author":[{"given":"Matthew J.","family":"Butcher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rama 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