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However, the contribution of the Y chromosome-encoded epigenetic regulator UTY (also known as KDM6C) to male NK cell development and effector function remains poorly characterized. Here, we demonstrated that conditional deletion of UTY in NK cells (Ncr1-iCre) in male mice led to a statistically significant but modest increase in total NK cell numbers (P\u2009&amp;lt;\u20090.05) and an elevated frequency of terminally differentiated CD27\u2212CD11b+ subset in the spleen. Strikingly, UTY-deficient NK cells displayed impaired cytotoxic function, with significantly reduced granzyme B expression (P\u2009&amp;lt;\u20090.05) and attenuated control of B16F10 melanoma pulmonary metastases in vivo (P\u2009&amp;lt;\u20090.05). Importantly, combined UTX-UTY deficiency exacerbated these phenotypes, causing further increase in NK cell abundance, and decline in CD27+CD11b+ subset proportions and granzyme B expression level compared with UTX single knockout in male mice. RNA-sequencing combined with qRT-PCR validation uncovered significant downregulation of key genes involved in NK cell maturation (Cd27), cytotoxicity (Gzmb), survival (Bax, Casp3) and transcriptional regulation (Socs3, Tcf7, Fos) in UTY-deficient NK cells. Notably, dual UTX-UTY depletion synergistically repressed Casp3 expression, potentially contributing to the altered NK cell abundance (P\u2009&amp;lt;\u20090.05). These findings establish UTY as a sex-specific epigenetic modulator that restricts NK cell maturation while promoting cytotoxic function. Our data further reveal a cooperative role for UTY and UTX in orchestrating NK cell development via transcriptional regulation.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf248","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T21:50:25Z","timestamp":1758318625000},"source":"Crossref","is-referenced-by-count":6,"title":["UTY coordinates with UTX to repress NK cell development and maturation in males"],"prefix":"10.1093","volume":"215","author":[{"given":"Pei","family":"Huang","sequence":"first","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Guan","sequence":"additional","affiliation":[{"name":"Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongxi","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"He","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology, the 940th Hospital of Joint Logistics Support Force of the Chinese People\u2019s Liberation Army , Lanzhou,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangyu","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Die","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University , 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Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qinghua","family":"Bi","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Clinical Hematology, College of Pharmacy and Laboratory Medicine Science, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhifeng","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaping","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qintao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jijian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyan","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of High-Altitude Operational Medicine, College of High-Altitude Military Medicine, Key Laboratory of Extreme Environmental Medicine, Ministry of Education, Army Medical University , Chongqing,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxu","family":"Li","sequence":"additional","affiliation":[{"name":"Department of High-Altitude 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through noncatalytic inverse regulation of ETS and GATA programs","volume":"50","author":"Gozdecka","year":"2018","journal-title":"Nat Genet"},{"key":"2026012707073600200_vkaf248-B13","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1016\/j.ccell.2018.02.003","article-title":"Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors","volume":"33","author":"Andricovich","year":"2018","journal-title":"Cancer Cell"},{"key":"2026012707073600200_vkaf248-B14","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1038\/s41590-023-01463-8","article-title":"The X-linked epigenetic regulator UTX controls NK cell-intrinsic sex differences","volume":"24","author":"Cheng","year":"2023","journal-title":"Nat Immunol"},{"key":"2026012707073600200_vkaf248-B15","doi-asserted-by":"crossref","first-page":"41854","DOI":"10.18632\/oncotarget.16688","article-title":"Chromatin state dynamics during NK cell 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