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

نویسندگان

  • Antoine Marçais
  • Marie Marotel
  • Sophie Degouve
  • Alice Koenig
  • Sébastien Fauteux-Daniel
  • Annabelle Drouillard
  • Heinrich Schlums
  • Sébastien Viel
  • Laurie Besson
  • Omran Allatif
  • Mathieu Bléry
  • Eric Vivier
  • Yenan Bryceson
  • Olivier Thaunat
  • Thierry Walzer
چکیده

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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عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2017