The cytotoxic properties of NK cells make them critical for immune surveillance and acute defence from pathogens, but pose risk to the host if unrestrained. NK cell cytotoxic activity is controlled through an extensive network of internal checkpoints that regulate their behaviour. While an arsenal of activating and inhibitory receptors restricts execution of cytotoxicity toward only hazardous targets, cytokines dictate a majority of NK cell behaviours during infection and the steady state. Deeper and more precise investigation of such cytokines and their influence on NK cell behaviour will likely offer vital insight into the regulatory networks that control NK cells.
To this end, we used a refined series of quantitative cellular calculus methods to dissect the biological outcomes of NK cells following stimulation with cytokines. Using such methods, we have uncovered a predisposition for early cell death in NK cells stimulated with IL-15 alone, or combinations of IL-15, IL-18 and IL-12. This cytokine-induced cell death was dependent on expression of Fas ligand (FasL), a death-inducing protein expressed by cytotoxic cells and used to eliminate targets. The expression of FasL and its cognate death receptor Fas on NK cells increased during IL-15/18 and IL-12/15/18 stimulation, facilitating the killing of Fas-expressing NK cells. This work offers insight into the nature of NK cell activation and poses valuable implications for therapies requiring NK cell stimulation.