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.
The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut
Disclosures: The authors declare no competing interests exist.
- Award Id(s): 310030_179235
- Award Id(s): KFS-4398-02-2018,KFS-5402-08-2021
- Award Id(s): N-403-06-26 HCP
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Ewelina Krzywinska, Michal Sobecki, Shunmugam Nagarajan, Julian Zacharjasz, Murtaza M. Tambuwala, Abigaelle Pelletier, Eoin Cummins, Dagmar Gotthardt, Joachim Fandrey, Yann M. Kerdiles, Carole Peyssonnaux, Cormac T. Taylor, Veronika Sexl, Christian Stockmann; The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut. J Exp Med 7 February 2022; 219 (2): e20210909. doi: https://doi.org/10.1084/jem.20210909
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