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.
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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).
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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