Linoleic Acid Enhances Murine Natural Killer Cell Function In Vitro but Compromises Mitochondrial Bioenergetic Function During Retroviral Infection

Natural killer (NK) cells are innate immune cells that eliminate virus-infected and tumour cells by a plethora of signalling pathways, involving the production of cytokines and cytotoxic molecules. NK cell activation and functions demand substantial energy and fatty acids are energy-rich molecules reported to be important for NK cell functions upon viral infections. However, it remains unclear whether NK cells preferentially take up a specific fatty acid. Here, we show in the acute Friend retrovirus infection of mice that linoleic acid (LA) exerts a dual role in modulating NK cells. Interestingly, NK cells increased the uptake of LA upon virus infection in vitro and in vivo, with higher LA uptake correlating with increased activation of NK cells. While ex vivo stimulation with LA increased the expression of cytolytic molecules and subsequently elicited increased target cell killing, it paradoxically decreased the NK cell proliferative capacity, mitochondrial metabolism and increased the cellular stress. To further elucidate the role of LA in vivo, we treated mice with exogenous LA during retrovirus infection. While we observed a significant increase of LA levels in the spleen, splenic NK cell activation, cytotoxicity and viral loads were not altered by LA therapy. In addition, we found a decrease in mitochondrial mass and energy levels in NK cells after LA treatment, reflecting its strong effect on mitochondrial metabolism. Our results demonstrate the importance and direct impact of LA for NK cell functions and their metabolic profile. The dual role of LA in enhancing NK cell responses while compromising mitochondrial integrity highlights its potential as a therapeutic adjuvant, alongside other fatty acids, to modulate NK cell functions.