Abstract

The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1α and HIF2α) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2ΔTreg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-γ in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing a Th1-like effector phenotype. Concomitantly, the expression of innate-type cytokines such as Il1b, Il12a, Il12b and Tnfa was found to be elevated in peripheral (gut) tissues and spleen. PHD2ΔTreg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs did not efficiently control inflammatory response in vivo, in particular those characterized by IFN-γ production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2α (PHD2-HIF2αΔTreg mice), but not in PHD2-HIF1α (PHD2-HIF1αΔTreg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2α axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs identified the STAT1 pathway as a target of the PHD2-HIF2α axis in regulatory T cell phenotype and in vivo function.

Data availability

Sequencing data have been deposited in GEO under accession code GSE18458.Numerical data used to generate the figures have been provided for Figures 1-8 and S1-S8 (named Source data Figure 1 - Figure S8).

Article and author information

Author details

  1. Yousra Ajouaou

    Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1734-6505
  2. Abdulkader Azouz

    Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  3. Anaëlle Taquin

    Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  4. Sebastien Denanglaire

    Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  5. Hind Hussein

    Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Mohammad Krayem

    Department of Radiation Oncology, Université Libre de Bruxelles, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  7. Fabienne Andris

    Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8644-1020
  8. Muriel Moser

    Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  9. Stanislas Goriely

    Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  10. Oberdan Leo

    Université Libre de Bruxelles, Gosselies, Belgium
    For correspondence
    oberdan.leo@ulb.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3621-4743

Funding

European Regional Development Fund

  • Yousra Ajouaou
  • Hind Hussein
  • Fabienne Andris
  • Muriel Moser
  • Stanislas Goriely
  • Oberdan Leo

Fond de la recherche scientifique

  • Yousra Ajouaou
  • Hind Hussein

Walloon region

  • Fabienne Andris
  • Muriel Moser
  • Stanislas Goriely
  • Oberdan Leo

Fond Jean Brachet

  • Fabienne Andris
  • Muriel Moser
  • Stanislas Goriely
  • Oberdan Leo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Peter J Ratcliffe, University of Oxford, United Kingdom

Ethics

Animal experimentation: The experiments were performed in compliance with the relevant laws and institutional guidelines and were approved by the Local Ethic Committee. We received specific approval for this study from the Université Libre de Bruxelles Institutional Animal Care and Use Committee (protocol numbers CEBEA-4 and 31).

Version history

  1. Preprint posted: March 23, 2021 (view preprint)
  2. Received: June 12, 2021
  3. Accepted: February 18, 2022
  4. Accepted Manuscript published: February 22, 2022 (version 1)
  5. Version of Record published: March 4, 2022 (version 2)

Copyright

© 2022, Ajouaou et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yousra Ajouaou
  2. Abdulkader Azouz
  3. Anaëlle Taquin
  4. Sebastien Denanglaire
  5. Hind Hussein
  6. Mohammad Krayem
  7. Fabienne Andris
  8. Muriel Moser
  9. Stanislas Goriely
  10. Oberdan Leo
(2022)
The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells
eLife 11:e70555.
https://doi.org/10.7554/eLife.70555

Share this article

https://doi.org/10.7554/eLife.70555

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