High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors
- International Center for Infectiology Research (CIRI), France
- Karolinska Institutet, Karolinska University Hospital Huddinge, Sweden
- Innate Pharma, France
- Aix Marseille Université, France
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
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
- Wayne M Yokoyama, Howard Hughes Medical Institute, Washington University School of Medicine, United States
Publication history
- Received: February 28, 2017
- Accepted: August 29, 2017
- Accepted Manuscript published: September 6, 2017 (version 1)
- Version of Record published: October 4, 2017 (version 2)
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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High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors
eLife 6:e26423.
https://doi.org/10.7554/eLife.26423
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