Resting natural killer cell homeostasis relies on tryptophan/ NAD + metabolism and HIF ‐1α

Abstract

Natural killer (NK) cells are forced to cope with different oxygen environments even under resting conditions. The adaptation to low oxygen is regulated by oxygen‐sensitive transcription factors, the hypoxia‐inducible factors (HIFs). The function of HIFs for NK cell activation and metabolic rewiring remains controversial. Activated NK cells are predominantly glycolytic, but the metabolic programs that ensure the maintenance of resting NK cells are enigmatic. By combining in situ metabolomic and transcriptomic analyses in resting murine NK cells, our study defines HIF‐1α as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD + ) levels. The HIF‐1α/NAD + axis prevents ROS production during oxidative phosphorylation (OxPhos) and thereby blocks DNA damage and NK cell apoptosis under steady‐state conditions. In contrast, in activated NK cells under hypoxia, HIF‐1α is required for glycolysis, and forced HIF‐1α expression boosts glycolysis and NK cell performance in vitro and in vivo . Our data highlight two distinct pathways by which HIF‐1α interferes with NK cell metabolism. While HIF‐1α‐driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF‐1α‐dependent tryptophan/NAD + metabolism. image The transcription factor HIF‐1α has a role in the tryptophan/NAD + pathway that ensures redox homeostasis of resting Natural Killer (NK) cells. Upon activation, forced HIF‐1α‐driven glycolysis enhances NK cell effector potential. HIF‐1α differentially interferes with the metabolism of resting and activated NK cells via two distinct pathways. In resting NK cells, HIF‐1α has a previously unanticipated role in tryptophan metabolism and the maintenance of free NAD + levels. During NK cell activation HIF‐1α‐driven glycolysis is essential for full effector function. Forced activation of HIF‐1α can enhance the anti‐metastatic action of NK cells in vivo .