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Cell. 2011 Sep 2;146(5):772-84. doi: 10.1016/j.cell.2011.07.033. Epub 2011 Aug 25.

Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1.

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  • 1Immunology and Hematopoiesis Division, Department of Oncology and Medicine, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Maryland 21231, USA.

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 T(H)17 differentiation. HIF-1 enhances T(H)17 development through direct transcriptional activation of RORγt and via tertiary complex formation with RORγt and p300 recruitment to the IL-17 promoter, thereby regulating T(H)17 signature genes. Concurrently, HIF-1 attenuates T(reg) 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(H)17-dependent experimental autoimmune encephalitis associated with diminished T(H)17 and increased T(reg) 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.

Copyright © 2011 Elsevier Inc. All rights reserved.

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PMID:
21871655
[PubMed - indexed for MEDLINE]
PMCID:
PMC3387678
Free PMC Article

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