Hypoxia-inducible factor 2a promotes protective Th2 cell responses during intestinal helminth infection [RNA-seq]
Th2 cells must sense and adapt to the tissue milieu in order 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 (HIF2a). In vitro, exposure to hypoxia or genetic HIF2a activation promoted Th2 cell differentiation, even under non-polarizing conditions. In mice, HIF2a activation in CD4+ T cells promoted intestinal Th2 cell accumulation in the absence of infection, and HIF2a-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 2a (HIF2a), as key regulators of Th2 cell differentiation and function within the small intestine. Overall design: 3 technical replicates of 8 conditions, being Th0 normoxia ctrl, Th0 normoxia HIF2A-ON, Th0 hypoxia ctrl, Th0 hypoxia HIF2A-ON, Th2 normoxia ctrl, Th2 normoxia HIF2A-ON, Th2 hypoxia ctrl, Th2 hypoxia HIF2A-ON.