HIF-2? is indispensable for regulatory T cell function.

ABSTRACT: Hypoxia-inducible factor 1? (HIF-1?) and HIF-2? are master transcription factors that regulate cellular responses to hypoxia, but the exact function in regulatory T (Treg) cells is controversial. Here, we show that Treg cell development is normal in mice with Foxp3-specific knockout (KO) of HIF-1? or HIF-2?. However, HIF-2?-KO (but not HIF-1?-KO) Treg cells are functionally defective in suppressing effector T cell-induced colitis and inhibiting airway hypersensitivity. HIF-2?-KO Treg cells have enhanced reprogramming into IL-17-secreting cells. We show crosstalk between HIF-2? and HIF-1?, and that HIF-2? represses HIF-1? expression. HIF-1? is upregulated in HIF-2?-KO Treg cells and further deletion of HIF-1? restores the inhibitory function of HIF-2?-KO Treg cells. Mice with Foxp3-conditional KO of HIF-2? are resistant to growth of MC38 colon adenocarcinoma and metastases of B16F10 melanoma. Together, these results indicate that targeting HIF-2? to destabilize Treg cells might be an approach for regulating the functional activity of Treg cells.

SUBMITTER: Hsu TS 

PROVIDER: S-EPMC7538433 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature