TY - JOUR TI - HIF-2α is indispensable for regulatory T cell function AU - Hsu, Tzu-Sheng AU - Lin, Yen-Lin AU - Wang, Yu-An AU - Mo, Shu-Ting AU - Chi, Po-Yu AU - Lai, Alan Chuan-Ying AU - Pan, Hsuan-Yin AU - Chang, Ya-Jen AU - Lai, Ming-Zong T2 - Nature Communications AB - Hypoxia-inducible factor 1α (HIF-1α) and HIF-2α 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-1α or HIF-2α. However, HIF-2α-KO (but not HIF-1α-KO) Treg cells are functionally defective in suppressing effector T cell-induced colitis and inhibiting airway hypersensitivity. HIF-2α-KO Treg cells have enhanced reprogramming into IL-17-secreting cells. We show crosstalk between HIF-2α and HIF-1α, and that HIF-2α represses HIF-1α expression. HIF-1α is upregulated in HIF-2α-KO Treg cells and further deletion of HIF-1α restores the inhibitory function of HIF-2α-KO Treg cells. Mice with Foxp3-conditional KO of HIF-2α are resistant to growth of MC38 colon adenocarcinoma and metastases of B16F10 melanoma. Together, these results indicate that targeting HIF-2α to destabilize Treg cells might be an approach for regulating the functional activity of Treg cells. DA - 2020/10/06/ PY - 2020 DO - 10.1038/s41467-020-18731-y DP - www.nature.com VL - 11 IS - 1 SP - 5005 LA - en SN - 2041-1723 UR - https://www.nature.com/articles/s41467-020-18731-y Y2 - 2020/10/06/18:28:00 ER -