Hypoxia enhances ILC3 responses through HIF-1α-dependent mechanism

Mucosal Immunol. 2021 Jul;14(4):828-841. doi: 10.1038/s41385-020-00371-6. Epub 2021 Jan 14.


Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa homeostasis. The hypoxia-inducible factor (HIF) is an important modulator of immune cell activation and a key mechanism for cellular adaptation to oxygen deprivation. However, its role on ILC3 is not well known. In this study, we investigated how a hypoxic environment modulates ILC3 response and the subsequent participation of HIF-1 signaling in this process. We found increased proliferation and activation of intestinal ILC3 at low oxygen levels, a response that was phenocopied when HIF-1α was chemically stabilized and was reversed when HIF-1 was blocked. The increased activation of ILC3 relied on a HIF-1α-dependent transcriptional program, but not on mTOR-signaling or a switch to glycolysis. HIF-1α deficiency in RORyt compartment resulted in impaired IL-17 and IL-22 production by ILC3 in vivo, which reflected in a lower expression of their target genes in the intestinal epithelium and an increased susceptibility to Clostridiodes difficile infection. Taken together, our results show that HIF-1α activation in intestinal ILC3 is relevant for their functions in steady state and infectious conditions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Clostridium Infections / etiology
  • Clostridium Infections / metabolism
  • Disease Models, Animal
  • Disease Susceptibility
  • Hypoxia / immunology*
  • Hypoxia / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Immunity, Innate*
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Lymphocyte Subsets / immunology*
  • Lymphocyte Subsets / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Protein Stability
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • TOR Serine-Threonine Kinases