Molecular determinants of NK cell memory

Natural killer (NK) cells are innate lymphocytes uniquely equipped with stochastically expressed activating and inhibitory receptors that shape their cytotoxic potential. Although traditionally viewed as rapid and potent innate effectors against infected or transformed cells, we now appreciate that NK cells possess adaptive capabilities, such as antigen-specific clonal expansion and the generation of long-lived memory cells. The ability of NK cells to engage in innate and adaptive immune responses is tightly coordinated by a 'three-signal' framework that relies on the synergy between NK cell receptor engagement (signal 1), co-stimulation (signal 2), and cytokine-mediated signals (signal 3). This review focuses on knowledge gleaned from emerging molecular pathways aimed at modulating signals 1, 2, and 3 to reprogram NK cells for therapeutic utility.