HIF-2α is indispensable for regulatory T cell function

Tzu-Sheng Hsu, Yen-Lin Lin, Yu-An Wang, Shu-Ting Mo, Po-Yu Chi, Alan Chuan-Ying Lai, Hsuan-Yin Pan, Ya-Jen Chang and Ming-Zong Lai ()
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Tzu-Sheng Hsu: Institute of Molecular Biology, Academia Sinica
Yen-Lin Lin: Institute of Molecular Biology, Academia Sinica
Yu-An Wang: Institute of Molecular Biology, Academia Sinica
Shu-Ting Mo: Institute of Molecular Biology, Academia Sinica
Po-Yu Chi: Institute of Biomedical Sciences, Academia Sinica
Alan Chuan-Ying Lai: Institute of Biomedical Sciences, Academia Sinica
Hsuan-Yin Pan: Institute of Molecular Biology, Academia Sinica
Ya-Jen Chang: Institute of Biomedical Sciences, Academia Sinica
Ming-Zong Lai: Institute of Molecular Biology, Academia Sinica

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-18731-y

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