Control of TH17/Treg balance by hypoxia-inducible factor 1

Eric V. Dang, Joseph Barbi, Huang Yu Yang, Dilini Jinasena, Hong Yu, Ying Zheng, Zachary Bordman, Juan Fu, Young Kim, Hung Rong Yen, Weibo Luo, Karen Zeller, Larissa Shimoda, Suzanne L. Topalian, Gregg L. Semenza, Chi V. Dang, Drew M. Pardoll, Fan Pan

Research output: Contribution to journalArticle

Abstract

T cell differentiation into distinct functional effector and inhibitory subsets is regulated, in part, by the cytokine environment present at the time of antigen recognition. Here, we show that hypoxia-inducible factor 1 (HIF-1), a key metabolic sensor, regulates the balance between regulatory T cell (T reg) and TH17 differentiation. HIF-1 enhances T H17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating TH17 signature genes. Concurrently, HIF-1 attenuates Treg development by binding Foxp3 and targeting it for proteasomal degradation. Importantly, this regulation occurs under both normoxic and hypoxic conditions. Mice with HIF-1α-deficient T cells are resistant to induction of T H17-dependent experimental autoimmune encephalitis associated with diminished TH17 and increased Treg cells. These findings highlight the importance of metabolic cues in T cell fate determination and suggest that metabolic modulation could ameliorate certain T cell-based immune pathologies.

Original languageEnglish (US)
Pages (from-to)772-784
Number of pages13
JournalCell
Volume146
Issue number5
DOIs
StatePublished - Sep 2 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Dang, E. V., Barbi, J., Yang, H. Y., Jinasena, D., Yu, H., Zheng, Y., Bordman, Z., Fu, J., Kim, Y., Yen, H. R., Luo, W., Zeller, K., Shimoda, L., Topalian, S. L., Semenza, G. L., Dang, C. V., Pardoll, D. M., & Pan, F. (2011). Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell, 146(5), 772-784. https://doi.org/10.1016/j.cell.2011.07.033