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

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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Submitted on : Friday, October 26, 2018 - 9:44:25 AM
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Antoine Marçais, Marie Marotel, Sophie Degouve, Alice Koenig, Sebastien Fauteux-Daniel, et al.. High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors. eLife, eLife Sciences Publication, 2017, 6, ⟨10.7554/eLife.26423⟩. ⟨hal-01764666⟩

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