Boosting vaccine efficacy the natural (killer) way

•Vaccination should induce long-lived protective B, T, and NK cell immunity.•NK cells can positively and negatively regulate adaptive immunity.•The mechanism and nature of NK cell immunomodulation are context dependent.•Memory and regulatory NK cell activities should be targeted in immunization.

Coordination of the innate and adaptive immune systems is paramount to the development of protective humoral and cellular immunity following vaccination. Natural killer (NK) cells are front-line soldiers of the innate immune system, and recent studies have revealed functions for NK cells in long-lived immune memory and the regulation of adaptive immune responses. These findings suggest that NK cells may play important roles in the development of efficacious vaccines, as well as, in some contexts, failed immunizations. Here, we review the current understanding of the immunomodulatory and memory differentiation capabilities of NK cells. We examine the context dependency of the mechanisms and the nature of NK cell-mediated modulation of the immune response, and discuss how these insights may impact immunization strategies and the development of next-generation vaccines.