The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut

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

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Abstract

Gut innate lymphoid cells (ILCs) show diverse phenotypes even after terminal differentiation,
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.
Original languageEnglish
Article numbere20210909
JournalJournal of Experimental Medicine
Volume219
Issue number2
Early online date13 Jan 2022
DOIs
Publication statusE-pub ahead of print - 13 Jan 2022

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