HIF-2α is indispensable for regulatory T cell function

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) and HIF-2 alpha 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 alpha or HIF-2 alpha. However, HIF-2 alpha -KO (but not HIF-1 alpha -KO) Treg cells are functionally defective in suppressing effector T cell-induced colitis and inhibiting airway hypersensitivity. HIF-2 alpha -KO Treg cells have enhanced reprogramming into IL-17-secreting cells. We show crosstalk between HIF-2 alpha and HIF-1 alpha, and that HIF-2 alpha represses HIF-1 alpha expression. HIF-1 alpha is upregulated in HIF-2 alpha -KO Treg cells and further deletion of HIF-1 alpha restores the inhibitory function of HIF-2 alpha -KO Treg cells. Mice with Foxp3-conditional KO of HIF-2 alpha are resistant to growth of MC38 colon adenocarcinoma and metastases of B16F10 melanoma. Together, these results indicate that targeting HIF-2 alpha to destabilize Treg cells might be an approach for regulating the functional activity of Treg cells. HIF-1 alpha is known to repress regulatory T (Treg) cell function, but less is known about the effect of HIF-2 alpha on these cells. Here, the authors use three different mouse models of inflammatory diseases to show that HIF-2 alpha limits HIF-1 alpha expression and is critical for Treg cell function.