mTORC1-Dependent Metabolic Reprogramming Is a Prerequisite for NK Cell Effector Function

Abstract

The mammalian target of rapamcyin complex 1 (mTORC1) is a key regulator of cellular metabolism and also has fundamental roles in controlling immune responses. Emerging evidence suggests that these two functions of mTORC1 are integrally linked. However, little is known regarding mTORC1 function in controlling the metabolism and function of natural killer (NK) cells, lymphocytes that play key roles in anti-viral and anti-tumour immunity. This study investigated the hypothesis that mTORC1-controlled metabolism underpins normal NK cell pro-inflammatory function. We demonstrate that mTORC1 is robustly stimulated in NK cells activated in vivo and in vitro. This mTORC1 activity is required for the production of the key NK cell effector molecules IFNγ, important in delivering antimicrobial and immunoregulatory functions, and granzyme B, a critical component of NK cell cytotoxic granules. The data reveal that NK cells undergo dramatic metabolic reprogramming upon activation, up-regulating rates of glucose uptake and glycolysis, and that mTORC1 activity is essential for attaining this elevated glycolytic state. Directly limiting the rate of glycolysis is sufficient to inhibit IFNγ production and granzyme B expression. This study provides the highly novel insight that mTORC1-mediated metabolic reprogramming of NK cells is a prerequisite for the acquisition of normal effector functions.

NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient

“…NK cells rely on metabolic reprogramming for effector function. Inhibition of either glycolysis or the glycolytic regulator mammalian target of rapamycin complex 1 (mTORC1) results in diminished effector responses by NK cells, such as cytokine production (21,22). Therefore, we investigated the effect of obesity on pediatric NK cell metabolic reprogramming.…”

“…NK cells isolated from obese children killed significantly fewer K562 tumor cells compared with their lean counterparts ( Figure 2H). We also investigated lytic molecule expression by NK cells after coculture with K562 and showed that NK cells from obese children express reduced levels of both granzyme B and perforin when compared with lean controls ( Recent studies have shown that NK cell effector function is intrinsically linked to cell metabolism (21,22). NK cells rely on metabolic reprogramming for effector function.…”

“…Furthermore, analysis of pediatric patients allows examination of immune function prior to onset of metabolic complications such as T2DM and thus may provide a good model for identification of mechanisms of obesity-related impaired immune function. Finally, it has recently been demonstrated that NK cell functions are affected by intrinsic cell metabolism (21,22). Therefore, we hypothesized that the altered environment in childhood obesity might affect NK cell metabolism and drive dysfunction.…”

Metabolic regulation of immune responses: therapeutic opportunities

“…The depletion of other nutrients may also indirectly impact glycolytic rates in immune cells by disrupting the activity of the metabolic regulator mTORC1 (22,23). Tryptophan and arginine can be depleted in the tumor microenvironment by the action of the enzymes indoleamine-pyrrole 2,3-dioxygenase (IDO) and arginase-1, respectively.…”

“…Preventing glycolytic metabolism in tumor-infiltrating effector lymphocytes by limiting glucose availability is one immune evasion strategy used by tumors (19)(20)(21). Disrupting glycolysis in effector T cells and NK cells inhibits the production of the proinflammatory cytokine IFN-γ and the expression of molecules important for cellular cytotoxicity (9,16,(22)(23)(24). Low glucose levels also enforce oxidative metabolism on tumor-infiltrating macrophages, which inhibits proinflammatory functions and promotes an antiinflammatory macrophage phenotype (25,26).…”