Conditional deletion of PGC-1α results in energetic and functional defects in NK cells

SUMMARY During an immune response, NK cells activate specific metabolic pathways to meet increased energetic and biosynthetic demands associated with effector functions. Here, we found in vivo activation of NK cells during Listeria monocytogenes infection augmented transcription of genes encoding mitochondria-associated proteins in a manner dependent upon the transcriptional coactivator PGC-1α. Using a Ncr1Cre-based conditional knockout mouse, we found PGC-1α was crucial for optimal NK cell effector functions and bioenergetics, as the deletion of PGC-1α was associated with decreased cytotoxic potential and cytokine production along with altered ADP/ATP ratios. Lack of PGC-1α also significantly impaired the ability of NK cells to control B16F10 tumor growth in vivo, and subsequent gene expression analysis showed PGC-1α mediates transcription required to maintain mitochondrial activity within the tumor microenvironment. Together, these data suggest PGC-1α-dependent transcription of specific target genes is required for optimal NK cell function during the response to infection or tumor growth.