T cell-specific HIF-2α attenuates colitis by antagonizing notch-driven Th2 differentiations.

Objective: The function of hypoxia-inducible factor-2α (HIF-2α) 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-2α to UC development. Methods: We immunohistochemically stained colonic biopsy tissues from human UC donors and healthy controls. A Lck-Cre-mediated Cre-loxP mediated HIF-2α conditional knockout mouse (HIF-2^ΔT/NKT) was generated and subjected to DSS-induced colitis induction. For mechanistic experiments, primary CD4 Results: Immunohistochemistry demonstrated increased HIF-2α 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 Conclusion: Our results establish a non-redundant protective function for T cell-intrinsic HIF-2α 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.