Natural killer (NK) cells are Innate Lymphoid Cells (ILC) involved in the immuno-surveillance of cancers and in the early control of infections by intracellular pathogens. 1 They can kill cells recognized as targets through a battery of surface receptors2 and produce large amounts of IFN-g upon activation. 1 They differentiate mainly in the Bone Marrow (BM) where sequential developmental intermediates, from immature to mature, can be defined on the basis of surface expression of the tumor necrosis factor (TNF) superfamily member CD27 and the integrin CD11b: CD11bloCD27hi NK cells, CD11bhiCD27hi and CD11bhiCD27lo. 3, 4 A hallmark of the NK cell population is their expression of high CD122 levels, the b subunit of the IL-2/IL-15 receptor underlining the fact that the various aspects of NK cell development, homeostasis and activation are conditioned by IL15. Despite this well acknowledged role, the molecular basis for the diversity of effects of IL-15 remains unknown. Metabolic integrators have recently emerged as key molecular players in immune cells differentiation. The metabolic checkpoint kinase mammalian Target Of Rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase integrating various extracellular cues: metabolite and growth factors but also antigenic and inflammatory signals and controlling in return numerous metabolic pathways. We recently reported that mTOR is essential for the proper differentiation and peripheral activation of NK cells and is activated upon NK cell exposure to IL-15. 5

Measuring the regulation of nutrient receptors expression as well as changes in respiratory and glycolytic rates, we showed that metabolism is gradually shut down upon NK cell differentiation in the BM leading to metabolically resting mature NK cells. In contrast, peripheral NK cell activation is characterized by an increase in metabolic activity. These results prompted us to analyze the phosphorylation status of mTOR targets by flow cytometry. We observed a perfect correlation between NK cell metabolism and mTOR activity. Submitting NK cells to a wide-range of stimuli in order to identify the signals able to control mTOR activity in NK cells, we showed that mTOR activity is triggered by IL-15 and by IL-18 to a lesser extent. In vivo blocking experiments demonstrated the paramount role of IL-15 in mTOR activation during development and following activation. Of note, mTOR activation necessitated high IL-15 concentrations in vitro; instead, STAT5 phosphorylation was readily triggered by low doses of IL-15.