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

Krzywinska et al. have studied the impact of the transcription factor HIF-1 alpha on the phenotype of intestinal NKp46(+) innate lymphoid cells and how it affects gut homeostasis. 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)-gamma-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-1 alpha isoform in NKp46(+) ILCs show a decrease in IFN-gamma-expressing, T-bet(+), NKp46(+) ILC1s and a concomitant increase in IL-22-expressing, ROR gamma t(+), NKp46(+) ILC3s in the gut mucosa. Single-cell RNA sequencing revealed HIF-1 alpha as a driver of ILC phenotypes, where HIF-1 alpha promotes the ILC1 phenotype by direct up-regulation of T-bet. Loss of HIF-1 alpha 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-1 alpha shapes the ILC phenotype in the gut.

Automated summary

In this study, the impact of transcription factor HIF-1 alpha on the phenotype of intestinal NKp46(+) innate lymphoid cells and its effects on gut homeostasis were investigated. The results showed that HIF-1 alpha plays a role in shaping the phenotype of ILCs in the gut, affecting the balance between ILC3s and ILC1s and conferring protection against intestinal damage.