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

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 (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. This submission contains 10x Gene Expression data from single CD4+ T cells sorted from the small intestine lamina propria of mice infected with the intestinal nematode parasite Heligmosomoides polygyrus or control uninfected mice. Samples were collected at 30 days post infection. Cells from multiple mice were pooled for each condition, and approximately 10,000 cells were captured from each pool.