TY - JOUR TI - High mTOR activity is a hallmark of reactive natural killer cells and amplifies early signaling through activating receptors AU - Marçais, Antoine AU - Marotel, Marie AU - Degouve, Sophie AU - Koenig, Alice AU - Fauteux-Daniel, Sébastien AU - Drouillard, Annabelle AU - Schlums, Heinrich AU - Viel, Sébastien AU - Besson, Laurie AU - Allatif, Omran AU - Bléry, Mathieu AU - Vivier, Eric AU - Bryceson, Yenan AU - Thaunat, Olivier AU - Walzer, Thierry A2 - Yokoyama, Wayne M VL - 6 PY - 2017 DA - 2017/09/06 SP - e26423 C1 - eLife 2017;6:e26423 DO - 10.7554/eLife.26423 UR - https://doi.org/10.7554/eLife.26423 AB - 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. KW - natural killer KW - cell signaling KW - mTOR KW - education KW - activation threshold JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -