Natural killer cell maturation is blocked by mTOR inhibition in C57Bl/6 mice

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Recent work established a pathway by which the energy sensitive kinase mammalian target of rapamycin (mTOR) regulates T cell biology, and this pathway is directly influenced by energy intake. Energy restriction (ER) is a dietary intervention shown to increase lifespan and reduce the incidence of tumors in rodents. The objective of this study was to examine the role of mTOR in NK cell metabolism and biology, based on the observation that ER results in fewer mature NK cells. NK cells from 40% ER mice exhibited mTOR inhibition directly ex vivo, and reduced expression of the transcription factors Eomes and T‐bet, which are required for NK cell maturation. Consequences of mTOR inhibition on NK cell biology was examined in vitro and revealed IL‐12 + IL‐18 induced NK cell maturation and function was impaired following rapamycin treatment. mTOR inhibition reduced upregulation of metabolic transporters, and repressed expression of NK cell maturation markers. Concurrently, mTOR inhibition in NK cells blocked upregulation of transcription factors Eomes and T‐bet following stimulation. Mature NK cells play a critical role in killing tumor cells and here we show NK cell maturation is linked to metabolic signaling through mTOR. Thus, manipulation of energy intake or energy sensitive pathways directly influences NK cell maturation, which has significant implications during the immune response to cancers or viral infections.Grant Funding Source: R01AG034949