PROJECT SUMMARY We propose to build upon exciting preliminary data highlighting unique effects natural killer (NK) cell subsets can have on regulating T cell responses using preclinical models of hematopoietic stem cell transplantation (HSCT), viral resistance, and cancer. While NK cells have been delineated into various subsets, the role of these subpopulations in viral and cancer resistance is unclear. We have built on numerous reports indicating that licensing or arming of the subsets based on MHC recognition gives rise to the various immunoregulatory functions they can exert on immune responses. We have found licensed and unlicensed NK cells to differentially affect T cell immune responses during viral infection and cancer acting as “helper” and “suppressor” populations. This proposal will seek to delineate the mechanisms underlying these effects on each other and T cells, assess the impact of HSCT and the role of the subsets in the context of cytomegalovirus infection and finally to link several species with regard to a molecular signature correlating with the subset phenotypes. Our first aim will build on this data and investigate the different mechanisms that NK cells can use to impact T cell responses during viral infection. The second aim will build on this concept of differential effects of NK subsets, but now examine how the immune environment established following HSCT can alter the effector roles observed as well as impact T cell recovery. The final aim will determine the impact CMV can have on NK subset reconstitution using both mouse and non-human primate models of autologous HSCT. This aim will also assess the impact of CMV on potential graft-versus-leukemia (GVL) effects following HSCT. Importantly, throughout the three aims, we will molecularly compare licensed and unlicensed NK cell subsets from multiple species including mouse, human, and non-human primate to link the common attributes of the subsets.