Cytokine activated NK cells acquire an elevated metabolic phenotype that is essential for robust NK cell anti-tumour responses. We have characterised the metabolic changes that occur in NK cells following cytokine stimulation; within 18 hours NK cells dramatically increase rates of glycolysis and OXPHOS and these changes are associated with an upregulation of the glycolytic machinery and increased mitochondrial mass. This increased metabolism supports cellular biosynthesis and energy production. Interestingly, NK cells are found to adopt a novel metabolic configuration that has not been described for any other lymphocyte subset. NK cells do not use the TCA cycle to drive OXPHOS, as is described in textbooks, but instead use the glucose-fuelled citrate malate shuttle. Our research has revealed the signal transduction pathways leading to this metabolic phenotype. The transcription factors Srebp and cMyc are essential for cytokine-induced metabolic and functional responses in murine NK cells. Srebp is required for the metabolic switch to the citrate-malate shuttle and cMyc promotes mitochondrial biogenesis and the increased expression of the glycolytic machinery. These discoveries help us to understand why NK cells are dysfunctional in various disease states including cancer and obesity where NK cell metabolism is found to be significantly perturbed.
Biography David Finlay
I first became captivated by the complexities of cellular signal transduction pathways during my undergraduate biochemistry degree at Trinity College Dublin, which led me to a PhD at the University of Dundee investigating roles for protein kinases such as mTORC1 in the control of metabolic pathways in hepatocytes. I retained a keen interest in protein kinase signalling during my postdoctoral research in Prof. Doreen Cantrell’s lab at the University of Dundee. It was during this time in I came to realise that mTORC1 is a key regulator of CD8 T cell biology largely because it controls cellular metabolic pathways. This led me to focus my research on understanding the relationship between immune cell metabolism and function. In 2011 I moved to Trinity College Dublin as a principle investigator and established an Immunometabolism research group studying metabolic regulation of Natural Killer cells and Dendritic cells.