Antoine Marçais , 1 , 2 , 3 , 4 , 5 , Marie Marotel 1 , 2 , 3 , 4 , 5 , Sophie Degouve 1 , 2 , 3 , 4 , 5 , Alice Koenig 1 , 2 , 3 , 4 , 5 , Sébastien Fauteux-Daniel 1 , 2 , 3 , 4 , 5 , Annabelle Drouillard 1 , 2 , 3 , 4 , 5 , Heinrich Schlums 6 , Sébastien Viel 1 , 2 , 3 , 4 , 5 , 7 , Laurie Besson 1 , 2 , 3 , 4 , 5 , Omran Allatif 1 , 2 , 3 , 4 , 5 , Mathieu Bléry 8 , Eric Vivier 9 , 10 , Yenan Bryceson 6 , 11 , Olivier Thaunat 1 , 2 , 3 , 4 , 5 , Thierry Walzer , 1 , 2 , 3 , 4 , 5
06 September 2017
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.
The cells of the immune system patrol the body to detect and destroy harmful microbes and diseased cells. Natural killer cells are immune cells with a natural capacity to kill infected or cancerous cells, as their name suggests. Importantly, they do so while sparing the surrounding healthy cells.
As natural killer cells mature they go through an “education” process to learn to distinguish between normal and abnormal cells. During education, the natural killer cells interact continuously with nearby healthy cells. However, it remains unknown how these interactions change the natural killer cells, or how these changes control their killing activity.
Marçais et al. now show that a protein called mTOR is essential to the education of natural killer cells. Comparing natural killer cells that had or had not completed the education process revealed that mTOR is more active in the educated cells. Moreover, inhibiting the activity of mTOR caused educated natural killer cells to lose their ability to identify diseased cells, while stimulating mTOR activity in uneducated natural killer cells mimicked the education process, allowing them to recognize and eliminate diseased host cells.
Certain nutrients are known to control the activity of mTOR, which suggests these nutrients could also affect how natural killer cells develop. In addition, manipulating the activity of mTOR could be used to control the response of natural killer cells to diseased host cells, and so could form part of treatments for cancer and infectious diseases. However, given that mTOR plays numerous roles within different body cells, any potential therapies that are developed would need to be able to manipulate mTOR specifically in natural killer cells.