Hypoxia-inducible factor 2α promotes protective Th2 cell responses during intestinal helminth infection

Abstract Th2 cells must sense and adapt to the tissue milieu to provide protective host immunity and tissue repair. Here, we examined the mechanisms promoting Th2 cell differentiation and function within the small intestinal lamina propria. Single cell RNA-seq analyses of CD4+ T cells from the small intestinal lamina propria of helminth infected mice revealed high expression of the gene Epas1, encoding the transcription factor hypoxia-inducible factor 2a (HIF2α). In vitro, exposure to hypoxia or genetic HIF2α activation promoted Th2 cell differentiation, even under non-polarizing conditions. In mice, HIF2α activation in CD4+ T cells promoted intestinal Th2 cell accumulation in the absence of infection, and HIF2α-deficiency impaired CD4+ T cell-mediated host immunity to intestinal helminth infection. Our findings identified hypoxia, and the oxygen-regulated transcription factor Hypoxia-Inducible Factor 2α (HIF2α), as key regulators of Th2 cell differentiation and function within the small intestine.