{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T07:10:47Z","timestamp":1772521847405,"version":"3.50.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"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:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The function of hypoxia-inducible factor-2\u03b1 (HIF-2\u03b1) in ulcerative colitis pathogenesis is subject to ongoing debate, with conflicting reports indicating either disease-promoting or beneficial roles. This investigation was designed to define the precise contribution of T lymphocyte-restricted HIF-2\u03b1 to UC development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We immunohistochemically stained colonic biopsy tissues from human UC donors and healthy controls. A Lck-Cre-mediated Cre-loxP mediated HIF-2\u03b1 conditional knockout mouse (HIF-2^\u0394T\/NKT) was generated and subjected to DSS-induced colitis induction. For mechanistic experiments, primary CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells were transduced with lentiviral vectors harboring HIF-2-directed shRNA or cDNA. Protein-Protein interactions, signal transduction and cellular phenotype were assessed by Co-IP, qPCR array, multi-parametric flow cytometry, immunoblotting and histology.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Immunohistochemistry demonstrated increased HIF-2\u03b1 expression in colonic tissues from UC patients, but its expression levels in lymphocyte subtypes were inversely correlated with the clinical disease severity. Mice with T\/NKT cell specific HIF-2 deletion were more susceptible to DSS colitis, associated with abrogated polarization of T helper cells towards the Th2 lineage. This led to upregulation of\n                      <jats:italic>Il4<\/jats:italic>\n                      and\n                      <jats:italic>Gata3<\/jats:italic>\n                      transcription, as well as increased production of IL-4 cytokine. Molecularly, HIF-2\u03b1 bound directly to the proteolytically cleaved form of Notch1 intracellular domain (NICD), leading to a decrease in NICD-induced transcriptional activity. Consistent with this mode of action, forced HIF-2\u03b1 expression in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells abrogatedJagged1-induced Th2 commitment\n                      <jats:italic>in vitro<\/jats:italic>\n                      . In contrast, HIF-2\u03b1 deficiency enhanced Notch pathway signaling, promoted Th2 polarization and exacerbated colonic inflammation\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results establish a non-redundant protective function for T cell-intrinsic HIF-2\u03b1 in ulcerative colitis. The protein directly engages Notch1-NICD to restrain Notch signal transduction, ultimately limiting pathological Th2 cell differentiation and ameliorating intestinal inflammation. These data reconcile prior contradictory findings by revealing a crucial cellular context-dependent mechanism.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1755068","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T06:49:44Z","timestamp":1772520584000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["T cell-specific HIF-2\u03b1 attenuates colitis by antagonizing notch-driven Th2 differentiations"],"prefix":"10.3389","volume":"17","author":[{"given":"Ting","family":"Gao","sequence":"first","affiliation":[{"name":"Emergency Department, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liangfeng","family":"Gao","sequence":"additional","affiliation":[{"name":"Emergency Department, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong 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