Natural killer (NK) cells, the third largest population of lymphocytes, contribute to host defense against viral infection and the establishment of tumors. NK cells are generally classified as innate immune cells because they do not undergo gene rearrangement for diversification and antigen-specific responses. NK cells are also thought to be short-lived similar to other non-memory type immune cells. Recently, we have identified a novel subset of human NK cells that have several adaptive immune features and potent anti-viral responsiveness. These cells are characterized by deficiency in the expression of signaling adaptor FcR?. Intriguingly, through the action of the Fc receptor CD16, these FcR?-deficient NK cells (termed g-NK cells) exhibit enhanced responsiveness to virus-infected target cells that are coated with antibody, compared to conventional NK cells. To date, g-NK cells have been observed at varying frequencies in approximately one-third of the healthy individuals tested, and follow-up studies showed that these cells are maintained for at least several months. Our preliminary data indicate that the presence of g-NK cells is strongly associated with prior infection by human cytomegalovirus (HCMV), a common herpesvirus that infects billions of people worldwide. The overall goals of this proposal are to understand how g-NK cells are generated and maintained, and how they function better than conventional NK cells in response to virus-infected target cells. Specifically, the proposed study will investigate 1) the role of HCMV infection in the generation of g-NK cells, 2) the persistence and stability of g-NK cells, and 3) the mechanisms underlying the enhanced responsiveness of g-NK cells to stimulation through CD16. Together, the studies in this proposal will not only increase our understanding of adaptive immune features of g-NK cells, including memory-like properties, but also provide new approaches for harnessing the power and therapeutic benefits of g-NK cells in clinical settings in the context of viral infection and cancer.