Type of publication:
Type of document:
Krzywinska, E; Sobecki, M; Nagarajan, S; Zacharjasz, J; Tambuwala, MM; Pelletier, A; Cummins, E; Gotthardt, D; Fandrey, J; Kerdiles, YM; Peyssonnaux, C; Taylor, CT; Sexl, V; Stockmann, C
The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut.
J Exp Med. 2022; 219(2):e20210909
Authors Vetmeduni Vienna:
Vetmed Research Units
Institute of Pharmacology and Toxicology
- Gut innate lymphoid cells (ILCs) show remarkable phenotypic diversity, yet microenvironmental factors that drive this plasticity are incompletely understood. The balance between NKp46+, IL-22-producing, group 3 ILCs (ILC3s) and interferon (IFN)-γ-producing group 1 ILCs (ILC1s) contributes to 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. Mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in IFN-γ-expressing, T-bet+, NKp46+ ILC1s and a concomitant increase in IL-22-expressing, RORγt+, NKp46+ ILC3s 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 up-regulation 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. Taken together, our results suggest that HIF-1α shapes the ILC phenotype in the gut.© 2022 Krzywinska et al.