NK cells play important roles in bacterial infection, either through secretion of pro-inflammatory mediators such as IFNγ or through direct bactericidal activity. While their roles as cytokine producers are important during the initial stages of infection, prolonged NK cell activation can have an aggravating role, leading to sepsis. Feedback communication between myeloid cells and NK cells is therefore, essential to prevent hyperinflammation in the host.

LPS-induced peritonitis is a useful tool to mimic NK cell metabolic and functional responses to infection with sepsis-causing bacteria such as E. coli. Peritoneal NK cells exhibited heightened rates of metabolism and cytokine production following immunisation of mice with high-dose LPS. However, these NK cells also showed significant accumulation of intracellular lipids, a feature often associated with NK cell dysfunction. Metabolic analysis revealed that peritoneal NK cells were not using these lipids as a fuel and were exhibiting low use of β-oxidation of fatty acids.

To investigate this effect more closely, NK cell-macrophage co-cultures were used. This revealed that direct cell-cell contact with LPS-stimulated macrophages was required to induce lipid droplet accumulation in NK cells, visualised by confocal microscopy. This was associated with impaired NK cell IFNγ production and metabolism, with no effect on NK cell cytotoxicity. Furthermore, these co-cultures revealed that NK cells were acquiring molecules such as CD36 from macrophages through trogocytosis. Moreover, irreversible inhibitors of de novo lipid synthesis revealed that the lipids present in NK cells were macrophage-derived. Specific inhibition of lipid synthesis by macrophages significantly rescued IFNγ production and metabolism by NK cells.

This study shows the complexity of macrophage-NK cell communication in infection, involving the sharing of proteins and other biomolecules, namely lipids, to control the subsequent immune response. It also suggests a novel macrophage-lipid-NK cell metabolic regulatory axis that can limit NK cell functions in infection.