yet, microenvironmental factors that drive this diversity are incompletely understood. The
balance between NKp46+ Interleukin (IL-)22-producing, group 3 ILCs (ILC3s) and Interferon
(IFN-)γ-producing group ILCs (ILC1s) contributes to epithelial barrier integrity and gut
homeostasis. The gut mucosa is characterized by physiological hypoxia and adaptation to low
oxygen is mediated by Hypoxia-inducible transcription factors (HIFs). However, the impact of
HIFs on ILC phenotype and gut homeostasis is not well understood. We found that mice lacking
the HIF-1α isoform in NKp46+ ILCs (HIF-1α KO) show a decrease in IFN-γ-expressing, T-box
expressed in T cells (T-bet)+, NKp46+ ILC1s and a concomitant increase in IL-22-expressing,
retinoic-acid-receptor-related orphan receptor γ (RORγt)+, NKp46+ ILC3 in the gut mucosa.
Single-cell RNA sequencing revealed HIF-1α as a driver of ILC phenotypes, where HIF-1α
promotes the ILC1 phenotype by direct upregulation of T-bet. Loss of HIF-1α in NKp46+ cells
prevents ILC3-to-ILC1 conversion, increases the expression of IL-22-inducible genes and
confers protection against intestinal damage. Consistently, constitutive activation of the HIF
pathway in NKp46+ cells decreased the expression of IL-22 and aggravates intestinal damage.
Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut.