1. Academic Validation
  2. HIF-2α is indispensable for regulatory T cell function

HIF-2α is indispensable for regulatory T cell function

  • Nat Commun. 2020 Oct 6;11(1):5005. doi: 10.1038/s41467-020-18731-y.
Tzu-Sheng Hsu 1 Yen-Lin Lin 1 Yu-An Wang 1 Shu-Ting Mo 1 Po-Yu Chi 2 Alan Chuan-Ying Lai 2 Hsuan-Yin Pan 1 Ya-Jen Chang 2 Ming-Zong Lai 3
Affiliations

Affiliations

  • 1 Institute of Molecular Biology, Academia Sinica, 11529, Taipei, Taiwan.
  • 2 Institute of Biomedical Sciences, Academia Sinica, 11529, Taipei, Taiwan.
  • 3 Institute of Molecular Biology, Academia Sinica, 11529, Taipei, Taiwan. mblai@gate.sinica.edu.tw.
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.

Figures
Products