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

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-1 alpha as a regulator of tryptophan metabolism and cellular nicotinamide adenine dinucleotide (NAD(+)) levels. The HIF-1 alpha/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-1 alpha is required for glycolysis, and forced HIF-1 alpha expression boosts glycolysis and NK cell performance in vitro and in vivo. Our data highlight two distinct pathways by which HIF-1 alpha interferes with NK cell metabolism. While HIF-1 alpha-driven glycolysis is essential for NK cell activation, resting NK cell homeostasis relies on HIF-1 alpha-dependent tryptophan/NAD(+) metabolism. 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.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.

Eidgenössische Technische Hochschule Zürich
Aix-Marseille Université
Universität Duisburg-Essen
Veterinärmedizinische Universität Wien
Universität Zürich
Universität Innsbruck
University of Duisburg Essen
Aix-Marseille Universite
Swiss Federal Institutes of Technology Domain
University of Zurich