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EZH2, a histone H3 lysine 27 (H3K27) methyltransferase, is known as a key regulator of Treg identity and suppressive function upon activation. Here, we demonstrate that the H3K27 lysine demethylase KDM6B, which catalyzes the opposing reaction to EZH2, is also required for Treg identity and function after activation. Treg-specific deletion of\n                    <jats:italic>Kdm6b<\/jats:italic>\n                    impaired tissue Treg fate and function. KDM6B was upregulated after T cell antigen receptor signaling in Tregs and contributed to the regulation of Treg-associated gene expression through both direct and indirect mechanisms. A subset of Treg functional genes were direct targets of KDM6B and were co-occupied by FOXP3 at\n                    <jats:italic>cis<\/jats:italic>\n                    -regulatory regions, where KDM6B recruitment limited H3K27me3 accumulation. More broadly, KDM6B-dependent H3K27 demethylation facilitated Treg gene expression programs that supported tissue Treg homeostasis.\n                  <\/jats:p>","DOI":"10.1172\/jci196022","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T18:30:13Z","timestamp":1782844213000},"source":"Crossref","is-referenced-by-count":0,"title":["T cell receptor signaling induces expression of lysine demethylase KDM6B to maintain Treg homeostasis"],"prefix":"10.1172","volume":"136","author":[{"given":"Minghong","family":"He","sequence":"first","affiliation":[{"name":"Department of Immunology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0099-858X","authenticated-orcid":true,"given":"Beisi","family":"Xu","sequence":"additional","affiliation":[{"name":"Center for Applied Bioinformatics, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pria G.","family":"Bose","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute,"},{"name":"Department of Pathology and Laboratory Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan J.","family":"McCullough","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute,"},{"name":"Department of Microbiology and Immunology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rani S.","family":"Sellers","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Zong","sequence":"additional","affiliation":[{"name":"Department of Immunology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Qi","sequence":"additional","affiliation":[{"name":"Center for Applied Bioinformatics, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna L.","family":"Banten","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute,"},{"name":"Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriya K.","family":"Tune","sequence":"additional","affiliation":[{"name":"Marsico Lung Institute,"},{"name":"Department of Medicine, Division of Pulmonary Diseases and Critical Care Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2979-9624","authenticated-orcid":true,"given":"Matthew P.","family":"Zimmerman","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve","family":"Mullins","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology,"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA."},{"name":"Department of Medicine, Division of Oncology, and"},{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0752-2130","authenticated-orcid":true,"given":"J. 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