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    Hypoxia-inducible factor-1 alpha–dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa


    Clambey, Eric T. and McNamee, Eóin N. and Westrich, Joseph A. and Glover, Louise and Campbell, Eric L. and Jedlicka, Paul and de Zoeten, Edwin F. and Cambier, John C. and Stenmark, Kurt R. and Colgan, S.P. and Eltzschig, Holger K. (2012) Hypoxia-inducible factor-1 alpha–dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proceedings of the National Academy of Sciences of the United States of America, 109 (41). E2784-E2793. ISSN 0027-8424

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    Abstract

    Recent studies have demonstrated dramatic shifts in metabolic supply-and-demand ratios during inflammation, a process resulting in localized tissue hypoxia within inflammatory lesions (“inflammatory hypoxia”). As part of the adaptive immune response, T cells are recruited to sites of inflammatory hypoxia. Given the profound effects of hypoxia on gene regulation, we hypothesized that T-cell differentiation is controlled by hypoxia. To pursue this hypothesis, we analyzed the transcriptional consequences of ambient hypoxia (1% oxygen) on a broad panel of T-cell differentiation factors. Surprisingly, these studies revealed selective, robust induction of FoxP3, a key transcriptional regulator for regulatory T cells (Tregs). Studies of promoter binding or loss- and gain-of-function implicated hypoxia-inducible factor (HIF)-1α in inducing FoxP3. Similarly, hypoxia enhanced Treg abundance in vitro and in vivo. Finally, Treg-intrinsic HIF-1α was required for optimal Treg function and Hif1a–deficient Tregs failed to control T-cell–mediated colitis. These studies demonstrate that hypoxia is an intrinsic molecular cue that promotes FoxP3 expression, in turn eliciting potent antiinflammatory mechanisms to limit tissue damage in conditions of reduced oxygen availability.

    Item Type: Article
    Keywords: lymphocyte; metabolism; TGF-beta;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 12594
    Identification Number: https://doi.org/10.1073/pnas.1202366109
    Depositing User: Eoin McNamee
    Date Deposited: 23 Mar 2020 12:22
    Journal or Publication Title: Proceedings of the National Academy of Sciences of the United States of America
    Publisher: National Academy of Sciences
    Refereed: Yes
    URI:

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