Regulation of mTOR, Metabolic Fitness, and Effector Functions by Cytokines in Natural Killer Cells

Abstract

The control of cellular metabolism is now recognized as key to regulate functional properties of immune effectors such as T or Natural Killer (NK) cells. During persistent infections or in the tumor microenvironment, multiple metabolic changes have been highlighted in T cells that contribute to their dysfunctional state or exhaustion. NK cells may also undergo major phenotypic and functional modifications when infiltrating tumors that could be linked to metabolic alterations. The mammalian target of rapamycin (mTOR) kinase is a central regulator of cellular metabolism. mTOR integrates various extrinsic growth or immune signals and modulates metabolic pathways to fulfill cellular bioenergetics needs. mTOR also regulates transcription and translation thereby adapting cellular pathways to the growth or activation signals that are received. Here, we review the role and regulation of mTOR in NK cells, with a special focus on cytokines that target mTOR such as IL-15 and TGF-β. We also discuss how NK cell metabolic activity could be enhanced or modulated to improve their effector anti-tumor functions in clinical settings.

Keywords: IL-15; NK cells; TGF-β; mTOR; metabolism.

Figure 1

TGF-β inhibits IL-15-driven natural killer (NK) cell effector functions at two distinct levels. TGF-β inhibits IL-15 induced mTORC1/2 activation and the subsequent metabolic increase as well as effect on effector functions (A). In addition, it also inhibits the transcription of Tbx21, an IL-15 target, thus resulting in decreased IFN-γ production and IL2Rβ level (B).