Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function

  1. Marie Bettonville
  2. Stefania d'Aria
  3. Kathleen Weatherly
  4. Paolo E Porporato
  5. Jinyu Zhang
  6. Sabrina Bousbata
  7. Pierre Sonveaux
  8. Michel Y Braun  Is a corresponding author
  1. Université Libre de Bruxelles, Belgium
  2. Université Catholique de Louvain, Belgium

Abstract

Energy metabolism is essential for T cell function. However, how persistent antigenic stimulation affects T cell metabolism is unknown. Here, we report that long-term in vivo antigenic exposure induced a specific deficit in numerous metabolic enzymes. Accordingly, T cells exhibited low basal glycolytic flux and limited respiratory capacity. Strikingly, blockade of inhibitory receptor PD-1 stimulated the production of IFNγ in chronic T cells, but failed to shift their metabolism towards aerobic glycolysis, as observed in effector T cells. Instead, chronic T cells appeared to rely on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to produce ATP for IFNγ synthesis. Check-point blockade, however, increased mitochondrial production of superoxide and reduced viability and effector function. Thus, in the absence of a glycolytic switch, PD-1-mediated inhibition appears essential for limiting oxidative metabolism linked to effector function in chronic T cells, thereby promoting survival and functional fitness.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Marie Bettonville

    Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  2. Stefania d'Aria

    Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  3. Kathleen Weatherly

    Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  4. Paolo E Porporato

    Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8519-1552
  5. Jinyu Zhang

    Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  6. Sabrina Bousbata

    Laboratory of Molecular Parasitology, Université Libre de Bruxelles, Gosslies, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  7. Pierre Sonveaux

    Pole of Pharmacology and Therapeutics, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  8. Michel Y Braun

    Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium
    For correspondence
    mbraun@ulb.ac.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1417-4189

Funding

Televie

  • Marie Bettonville
  • Stefania d'Aria
  • Kathleen Weatherly

Interuniversity Attraction Poles

  • Pierre Sonveaux
  • Michel Y Braun

European Research Council

  • Pierre Sonveaux

ARC from Communaute Francaise de Belgique

  • Pierre Sonveaux

Fonds De La Recherche Scientifique - FNRS

  • Pierre Sonveaux
  • Michel Y Braun

Fondation Belge contre le Cancer

  • Michel Y Braun

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

Ethics

Animal experimentation: This study was performed in strict accordance with the European Union Directive 2010/63/EU on the protection of animals used for scientific purposes. All of the animals were handled according to approved institutional animal care and use committee protocols. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Universite Libre de Bruxelles (Protocol Number: 03-2015).

Copyright

© 2018, Bettonville 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. Marie Bettonville
  2. Stefania d'Aria
  3. Kathleen Weatherly
  4. Paolo E Porporato
  5. Jinyu Zhang
  6. Sabrina Bousbata
  7. Pierre Sonveaux
  8. Michel Y Braun
(2018)
Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function
eLife 7:e30938.
https://doi.org/10.7554/eLife.30938

Share this article

https://doi.org/10.7554/eLife.30938

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