What Fuels Natural Killers? Metabolism and NK Cell Responses

Abstract

There is a growing appreciation that cellular metabolism is important in determining the course of lymphocyte responses. Additionally, changes in metabolic processes have been linked to dysfunctional lymphocyte functions in a number of different diseases. While most early studies of metabolic regulation of lymphocyte function focused on T lymphocytes, an understanding of how metabolic pathways impact upon natural killer (NK) cell responses is now starting to emerge. In this review article, we will discuss how cellular metabolism influences lymphocyte function with a particular focus upon NK cells.

Keywords: adaptive immune response; glucose; glycolysis and oxidative phosphorylation; innate immune response; mTORC1 signalling; metabolism; natural killer cells; tumor immunotherapy; viral infection.

Figure 1

The differing metabolic phenotypes of quiescent versus activated lymphocytes. (A) Adenosine triphosphate (ATP) is the key molecule that provides energy for cellular processes. Maintaining cellular ATP levels is essential for bioenergetic homeostasis and cell survival. Glucose, a key fuel source for mammalian cells, can be metabolized via two integrated metabolic pathways, glycolysis and oxidative phosphorylation (oxphos), that efficiently generate ATP. Glycolysis converts glucose to pyruvate that, following transportation into the mitochondria, is further metabolized to CO₂ by the Krebs cycle fueling oxphos and ATP synthesis. In addition to the breakdown of glucose via glycolysis, cells have the ability to metabolize alternative substrates including fatty acids by β-oxidation and glutamine by glutaminolysis, which feed into the Krebs cycle and drive oxphos. (B) Aerobic glycolysis supports biosynthetic processes of the cell as it allows the uptake of larger amounts of glucose and the maintenance of elevated glycolytic flux. Glycolytic intermediates are then diverted into various pathways for the synthesis of biomolecules that support biosynthetic processes. For instance, glucose-6-phosphate (G6P) generated by the first step in glycolysis can feed into the pentose phosphate pathway (PPP) to support nucleotide synthesis. This pathway also generates NADPH, a cofactor that is essential for various biosynthetic processes including lipid synthesis. Glucose can also be converted into cytoplasmic acetyl-CoA via citrate in the Krebs cycle for the production of cholesterol and fatty acids for lipid synthesis. Other glycolytic intermediates can also be converted into biomolecules used for protein and lipid synthesis. During aerobic glycolysis a significant proportion of pyruvate is also converted to lactate and secreted from the cell. Lactate export is important as it allows glycolysis to be sustained at an elevated rate. Alternative fuels including glutamine feed into the Krebs cycle and can also supply biomolecules for biosynthetic processes under certain conditions. DHAP, dihydroxyacetone phosphate, GP, glycerate 3-phosphate, Ser, serine; Ala, alanine.

Figure 2

Proposed bimodal model of natural killer (NK) cell activation. NK cells are best characterized for their rapid, early immune responses after exposure to pathogen. Among the important innate cytokines that activate NK cells are IL12, IL15, and IL18. NK cells carry out direct cytotoxicity of target cells and are potent producers of IFNγ. There are relatively modest changes in NK cell metabolism at these early time points suggesting that this first wave of NK activity relies on cells that are primed and ready to go without the need for substantial metabolic reprogramming. However, we know that NK cells can function at extended time periods beyond the first few days post-infection. IL2, produced by activated T cells, is one cytokine that is important in this process. IL2 drives mTORC1-dependent glycolytic reprogramming of NK cells which we believe is critical for the sustained effector functions of this second generation of NK cells, allowing them to work in parallel with the adaptive immune response.