biostudies-literatureCheng MIDOD | USA | MEDCOM | MRDC | U.S. Army Medical Research Acquisition ActivityNCATS NIH HHSHHS | NIH | National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK NIH HHSNIAID NIH HHSHHS | NIH | National Institute of Neurological Disorders and StrokeHHS | NIH | National Institute of Allergy and Infectious DiseasesNINDS NIH HHSNIGMS NIH HHS1069-1074https://www.ebi.ac.uk/biostudies/studies/S-EPMC10948288biostudies-literatureUnknown212(7)Hypoxia is a hallmark of inflammatory conditions (e.g., inflammatory bowel disease [IBD]), and adaptive responses have consequently evolved to protect against hypoxia-associated tissue injury. Because augmenting hypoxia-induced protective responses is a promising therapeutic approach for IBD, a more complete understanding of these pathways is needed. Recent work has demonstrated that the histone demethylase UTX is oxygen-sensitive, but its role in IBD is unclear. In this study, we show that hypoxia-induced deactivation of UTX downregulates T cell responses in mucosal inflammation. Hypoxia results in decreased T cell proinflammatory cytokine production and increased immunosuppressive regulatory T cells, and these findings are recapitulated by UTX deficiency. Hypoxia leads to T cell accumulation of H3K27me3 histone modifications, suggesting that hypoxia impairs UTX's histone demethylase activity to dampen T cell colitogenic activity. Finally, T cell-specific UTX deletion ameliorates colonic inflammation in an IBD mouse model, implicating UTX's oxygen-sensitive demethylase activity in counteracting hypoxic inflammation.Journal of immunology (Baltimore, Md. : 1950)Cutting Edge: Hypoxia Sensing by the Histone Demethylase UTX (KDM6A) Limits Colitogenic CD4+ T Cells in Mucosal Inflammation.PMC10948288R01 AI174519R01 DK119445R01 AI143894T32 GM007185PR200530T32 AI007323NS107851AI143894DK119445K12 TR004410R01 NS107851Hong LBustillos CSheikh SZChin SVo ASu MAChen BCheng MILuthers CRfalseCutting Edge: Hypoxia Sensing by the Histone Demethylase UTX (KDM6A) Limits Colitogenic CD4+ T Cells in Mucosal Inflammation.Hypoxia is a hallmark of inflammatory conditions (e.g., inflammatory bowel disease [IBD]), and adaptive responses have consequently evolved to protect against hypoxia-associated tissue injury. Because augmenting hypoxia-induced protective responses is a promising therapeutic approach for IBD, a more complete understanding of these pathways is needed. Recent work has demonstrated that the histone demethylase UTX is oxygen-sensitive, but its role in IBD is unclear. In this study, we show that hypoxia-induced deactivation of UTX downregulates T cell responses in mucosal inflammation. Hypoxia results in decreased T cell proinflammatory cytokine production and increased immunosuppressive regulatory T cells, and these findings are recapitulated by UTX deficiency. Hypoxia leads to T cell accumulation of H3K27me3 histone modifications, suggesting that hypoxia impairs UTX's histone demethylase activity to dampen T cell colitogenic activity. Finally, T cell-specific UTX deletion ameliorates colonic inflammation in an IBD mouse model, implicating UTX's oxygen-sensitive demethylase activity in counteracting hypoxic inflammation.2024-01-01T00:00:00Z2024 Apr2026-06-01T07:44:45.753Z2025-07-04T03:05:48.677ZS-EPMC109482883835364710.4049/jimmunol.2300550