Natural Killer (NK) cells are cytotoxic innate lymphocytes important in the response against intracellular pathogens and tumor cells. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signals, cytokine stimulation and nutrient availability. This integration is achieved by signaling hubs, such as the metabolic checkpoint kinase mechanistic target of rapamycin (mTOR). mTOR is a conserved protein kinase that controls cellular growth and metabolism in eukaryotic cells and, therefore, is essential for NK cells development and function. The objective of this PhD was to decipher the pathway regulating mTOR in primary NK cells. We show that interleukin 15 (IL-15) and IL-18, two cytokines that are key for NK cells activation, activate the mTOR complex 1 (mTORC1) in a synergic manner. This activation is essential for NK cell proliferation and metabolic reprogramming in vitro and in vivo. Through genetic and pharmacological approaches, we show that IL-15 and IL-18 activates mTORC1 in a non-canonical manner, independently of the molecular inhibitor TSC. Instead, mTORC1 activation relies on the concomitant activation of the PI3K-AKT and ERK pathways by IL-15 and a non-canonical p38-MK2/3 pathway by IL-18 in primary NK cells. These findings shed a new light on the activation of NK cells by cytokines, a knowledge that could be exploited to boost NK cell potential in therapeutic settings.
Gratuit
Disciplines