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High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors

  1. Antoine Marçais Is a corresponding author
  2. Marie Marotel
  3. Sophie Degouve
  4. Alice Koenig
  5. Sébastien Fauteux-Daniel
  6. Annabelle Drouillard
  7. Heinrich Schlums
  8. Sébastien Viel
  9. Laurie Besson
  10. Omran Allatif
  11. Mathieu Bléry
  12. Eric Vivier
  13. Yenan Bryceson
  14. Olivier Thaunat
  15. Thierry Walzer Is a corresponding author
  1. International Center for Infectiology Research (CIRI), France
  2. Karolinska Institutet, Karolinska University Hospital Huddinge, Sweden
  3. Innate Pharma, France
  4. Aix Marseille Université, France
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Cite as: eLife 2017;6:e26423 doi: 10.7554/eLife.26423

Abstract

NK cell education is the process through which chronic engagement of inhibitory NK cell receptors by self MHC-I molecules preserves cellular responsiveness. The molecular mechanisms responsible for NK cell education remain unclear. Here, we show that mouse NK cell education is associated with a higher basal activity of the mTOR/Akt pathway, commensurate to the number of educating receptors. This higher activity was dependent on the SHP-1 phosphatase and essential for the improved responsiveness of reactive NK cells. Upon stimulation, the mTOR/Akt pathway amplified signaling through activating NK cell receptors by enhancing calcium flux and LFA-1 integrin activation. Pharmacological inhibition of mTOR resulted in a proportional decrease in NK cell reactivity. Reciprocally, acute cytokine stimulation restored reactivity of hyporesponsive NK cells through mTOR activation. These results demonstrate that mTOR acts as a molecular rheostat of NK cell reactivity controlled by educating receptors and uncover how cytokine stimulation overcomes NK cell education.

Article and author information

Author details

  1. Antoine Marçais

    International Center for Infectiology Research (CIRI), Lyon, France
    For correspondence
    antoine.marcais@inserm.fr
    Competing interests
    No competing interests declared.
  2. Marie Marotel

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  3. Sophie Degouve

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  4. Alice Koenig

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  5. Sébastien Fauteux-Daniel

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  6. Annabelle Drouillard

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  7. Heinrich Schlums

    Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  8. Sébastien Viel

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  9. Laurie Besson

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  10. Omran Allatif

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  11. Mathieu Bléry

    Innate Pharma, Marseille, France
    Competing interests
    Mathieu Bléry, MB is employee of Innate-Pharma.
  12. Eric Vivier

    Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Marseille, France
    Competing interests
    Eric Vivier, EV is shareholder of Innate-Pharma.
  13. Yenan Bryceson

    Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
    Competing interests
    No competing interests declared.
  14. Olivier Thaunat

    International Center for Infectiology Research (CIRI), Lyon, France
    Competing interests
    No competing interests declared.
  15. Thierry Walzer

    International Center for Infectiology Research (CIRI), Lyon, France
    For correspondence
    thierry.walzer@inserm.fr
    Competing interests
    No competing interests declared.
    ORCID icon 0000-0002-0857-8179

Funding

Agence Nationale de la Recherche (ANR-16-CE15-0005-01 Bank)

  • Antoine Marçais

H2020 European Research Council (281025 Dironaki)

  • Thierry Walzer

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 carried out in accordance with the French recommendations in the Guide for the ethical evaluation of experiments using laboratory animals and the European guidelines 86/609/CEE. All experimental studies were approved by the bioethic local committee CECCAPP (Permit number: CECCAPP_ENS_2014_018).

Reviewing Editor

  1. Wayne M Yokoyama, Reviewing Editor, Howard Hughes Medical Institute, Washington University School of Medicine, United States

Publication history

  1. Received: February 28, 2017
  2. Accepted: August 29, 2017
  3. Accepted Manuscript published: September 6, 2017 (version 1)

Copyright

© 2017, Marçais 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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