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Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function

Hussein Shehade, Valérie Acolty, Muriel Moser and Guillaume Oldenhove
J Immunol August 15, 2015, 195 (4) 1372-1376; DOI: https://doi.org/10.4049/jimmunol.1402552
Hussein Shehade
Laboratoire d'Immunobiologie, Université Libre de Bruxelles, 6041 Gosselies, Belgium
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Valérie Acolty
Laboratoire d'Immunobiologie, Université Libre de Bruxelles, 6041 Gosselies, Belgium
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Muriel Moser
Laboratoire d'Immunobiologie, Université Libre de Bruxelles, 6041 Gosselies, Belgium
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Guillaume Oldenhove
Laboratoire d'Immunobiologie, Université Libre de Bruxelles, 6041 Gosselies, Belgium
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Abstract

Tissue hypoxia can occur in physiological and pathological conditions. When O2 availability decreases, the transcription factor hypoxia-inducible factor (HIF)-1α is stabilized and regulates cellular adaptation to hypoxia. The objective of this study was to test whether HIF-1α regulates T cell fate and to define the molecular mechanisms of this control. Our data demonstrate that Th1 cells lose their capacity to produce IFN-γ when cultured under hypoxia. HIF-1α−/− Th1 cells were insensitive to hypoxia, underlining a critical role for HIF-1α. Our results point to a role for IL-10, as suggested by the increased IL-10 expression at low O2 levels and the unchanged IFN-γ production by IL-10–deficient Th1 cells stimulated in hypoxic conditions. Accordingly, STAT3 phosphorylation is increased in Th1 cells under hypoxia, leading to enhanced HIF-1α transcription, which, in turn, may inhibit suppressor of cytokine signaling 3 transcription. This positive-feedback loop reinforces STAT3 activation and downregulates Th1 responses that may cause collateral damage to the host.

Footnotes

  • ↵1 M.M. and G.O. are cosenior authors.

  • This work was supported by grants from the Fonds National de la Recherche Scientifique/Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture, Wallonia, the Interuniversity Attraction Pole Programme, the Research Concerted Action, and the Fonds Jean Brachet.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    CA
    constitutively activated
    HA
    hemagglutinin
    HIF
    hypoxia-inducible factor
    KLH
    keyhole limpet hemocyanin
    ND
    nondegradable
    SOCS
    suppressor of cytokine signaling
    Treg
    regulatory T cell
    WT
    wild-type.

  • Received October 15, 2014.
  • Accepted June 23, 2015.
  • Copyright © 2015 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 195 (4)
The Journal of Immunology
Vol. 195, Issue 4
15 Aug 2015
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Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function
Hussein Shehade, Valérie Acolty, Muriel Moser, Guillaume Oldenhove
The Journal of Immunology August 15, 2015, 195 (4) 1372-1376; DOI: 10.4049/jimmunol.1402552

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Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function
Hussein Shehade, Valérie Acolty, Muriel Moser, Guillaume Oldenhove
The Journal of Immunology August 15, 2015, 195 (4) 1372-1376; DOI: 10.4049/jimmunol.1402552
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