PKM2 regulation of metabolism but not transcription is important for natural killer cell responses

Abstract

Natural Killer (NK) cells have an important role in immune responses to viruses and tumours. Integrating signal transduction and cellular metabolism is essential for effective NK cells responses. The PKM2 isoform of the glycolytic enzyme Pyruvate Kinase has described roles in regulating glycolytic flux and signal transduction, especially gene transcription. While PKM2 expression is robustly induced in activated NK cells, NK cells lacking PKM2 showed no defect in metabolism or anti-viral responses to MCMV infection. This lack of phenotype is explained by compensatory PKM1 expression in PKM2-null NK cells. NK cells lacking PKM2 also showed no alteration in transcriptome indicating that PKM2 does not function as a signalling molecule in NK cells. Pharmacological activation of PKM2 with TEPP-46 acutely increases the glycolytic activity indicating that NK cells tightly regulate the enzymatic activity of this enzyme. NK cells treated with TEPP-46 had impaired mitochondrial metabolism and proinflammatory cytokine production, indicating that regulation of PKM2 enzymatic activity is important for NK cell function. Indeed, NK cells treated with TEPP-46 had increased levels of reactive oxygen species production, indicating that PKM2 enzymatic activity might be required for NK cell redox homeostasis. Taken together our data indicate that PKM2 regulated metabolism, not transcriptional control, is required for optimal NK cell responses.