Seasonal influenza epidemics are a leading cause of morbidity and mortality worldwide, and while prophylactic immunization has proven the most efficient way to prevent influenza so far, influenza vaccines need to be reformulated each year to address the rapid emergence of immune escape mutations and do not provide complete protection. The threat of a pandemic, which arises from the spread of novel strains of influenza A viruses against which most individuals have no or limited immunity, is another major public-health concern. Therefore, innovative approaches to enhance prevention of influenza epidemics and pandemics are highly desirable. Classically, Natural Killer (NK) cells are viewed as nonspecific effector cells of the innate immune system that play critical role(s) in defense against nascent neoplasms and viral infections, including influenza virus infection. Unexpectedly, NK cells have recently been shown to also exhibit adaptive immune functions. In particular, antigen-specific memory NK cell responses have been demonstrated in mice and in nonhuman primates. Preliminary data presented in this application now show the first evidence of virus-specific NK cell responses in humans and suggest that immunization with live attenuated influenza strains enhances influenza- specific killing by NK cells. These exciting data suggest that harnessing influenza-specific NK cell function might significantly enhance the protective effect mediated by vaccines. However, whether human NK cells mount long-lived influenza-specific responses able to protect against infection with a broad range of influenza strains remains to be fully determined. Here, we propose to build on our preliminary data in humans and use humanized BLT mice to experimentally evaluate transferrable NK cell memory responses and investigate the overarching hypothesis that influenza-specific NK cells with potent antiviral activity develop in humans and can mediate protection against influenza. Those questions will be addressed through two Specific Aims: (i) To characterize influenza-specific NK cells in individuals receiving influenza vaccination; and (ii) To assess the capacity of human NK cells to mediate protective responses against influenza infection through recognition and recall of influenza antigens in humanized mice. The results of these innovative explorative studies could provide the rationale to harness antigen-specific NK cell responses to improve the design of future influenza vaccines.