Sterol regulatory element binding protein is a crucial regulator of natural killer cell metabolism and function

Abstract

Natural Killer (NK) cells are a lymphocyte subset that has a key role in anti-viral and anti-tumour immunity. While the concept of immunometabolism has recently been recognised as critical in determining functions of immune cell subsets, nothing is known regarding the regulation of NK cell metabolism. This study demonstrates for the first time that glucose metabolism is dramatically up-regulated in NK cells activated in vitro or in vivo. Rates of glucose uptake, glycolysis and mitochondrial respiration increase following cytokine stimulation, a response involving increased expression of glucose transporters and various glycolytic enzymes. mTORC1 regulated SREBP activity is identified as essential for IL-2/12 stimulated glycolysis in NK cells. Our data suggests that SREBP activity maintains cytosolic NAD+, required for elevated glycolysis, via the citrate-malate shuttle. In contrast, IL-2/12/18 stimulated NK cells maintain SREBP activity and elevated glycolysis through a mechanism independent of mTORC1 activity. Activation induced glycolysis is crucial for normal NK cell function and perturbations that limit the rate of glycolysis disrupt the production of the key NK cell effector molecules IFNγ and granzyme b. This study defines the metabolic signature associated with NK cell activation and demonstrates for the first time that NK cell metabolism directly impacts NK cell effector function. This study has identified ways in which virally infected and transformed cells can evade the immune response through targeting NK metabolism; targeting mTORC1 activity or disrupting SREBP signalling and NAD+ levels. Therefore with a greater understanding of NK cell metabolism we can strive towards improved therapeutics to restore immune homeostasis.Natural Killer (NK) cells are a lymphocyte subset that has a key role in anti-viral and anti-tumour immunity. While the concept of immunometabolism has recently been recognised as critical in determining functions of immune cell subsets, nothing is known regarding the regulation of NK cell metabolism. This study demonstrates for the first time that glucose metabolism is dramatically up-regulated in NK cells activated in vitro or in vivo. Rates of glucose uptake, glycolysis and mitochondrial respiration increase following cytokine stimulation, a response involving increased expression of glucose transporters and various glycolytic enzymes. mTORC1 regulated SREBP activity is identified as essential for IL-2/12 stimulated glycolysis in NK cells. Our data suggests that SREBP activity maintains cytosolic NAD+, required for elevated glycolysis, via the citrate-malate shuttle. In contrast, IL-2/12/18 stimulated NK cells maintain SREBP activity and elevated glycolysis through a mechanism independent of mTORC1 activity. Activation induced glycolysis is crucial for normal NK cell function and perturbations that limit the rate of glycolysis disrupt the production of the key NK cell effector molecules IFNγ and granzyme b. This study defines the metabolic signature associated with NK cell activation and demonstrates for the first time that NK cell metabolism directly impacts NK cell effector function. This study has identified ways in which virally infected and transformed cells can evade the immune response through targeting NK metabolism; targeting mTORC1 activity or disrupting SREBP signalling and NAD+ levels. Therefore with a greater understanding of NK cell metabolism we can strive towards improved therapeutics to restore immune homeostasis.Natural Killer (NK) cells are a lymphocyte subset that has a key role in anti-viral and anti-tumour immunity. While the concept of immunometabolism has recently been recognised as critical in determining functions of immune cell subsets, nothing is known regarding the regulation of NK cell metabolism. This study demonstrates for the first time that glucose metabolism is dramatically up-regulated in NK cells activated in vitro or in vivo. Rates of glucose uptake, glycolysis and mitochondrial respiration increase following cytokine stimulation, a response involving increased expression of glucose transporters and various glycolytic enzymes. mTORC1 regulated SREBP activity is identified as essential for IL-2/12 stimulated glycolysis in NK cells. Our data suggests that SREBP activity maintains cytosolic NAD+, required for elevated glycolysis, via the citrate-malate shuttle. In contrast, IL-2/12/18 stimulated NK cells maintain SREBP activity and elevated glycolysis through a mechanism independent of mTORC1 activity. Activation induced glycolysis is crucial for normal NK cell function and perturbations that limit the rate of glycolysis disrupt the production of the key NK cell effector molecules IFNγ and granzyme b. This study defines the metabolic signature associated with NK cell activation and demonstrates for the first time that NK cell metabolism directly impacts NK cell effector function. This study has identified ways in which virally infected and transformed cells can evade the immune response through targeting NK metabolism; targeting mTORC1 activity or disrupting SREBP signalling and NAD+ levels. Therefore with a greater understanding of NK cell metabolism we can strive towards improved therapeutics to restore immune homeostasis.