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

作者：Marcais Antoine^*; Marotel Marie; Degouve Sophie; Koenig Alice; Fauteux Daniel Sebastien; Drouillard Annabelle; Schlums Heinrich; Viel Sebastien; Besson Laurie; Allatif Omran; Blery Mathieu; Vivier Eric; Bryceson Yenan; Thaunat Olivier; Walzer Thierry^*

来源：eLife, 2017, 6: 264.

DOI：10.7554/eLife.26423

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.

• 出版日期2017-9-6