Natural killer (NK) cells are innate lymphocytes that play a critical role in controlling viral infections, coordinating the response of innate and adaptive immune systems. They also possess certain features of adaptive immunity, such as undergoing clonal proliferation and memory formation during viral infection. Although initial engagement of activating receptors and pro- inflammatory cytokine signaling are required to drive NK cell clonal expansion, additional stimulatory signals controlling their proliferation remain to be discovered. Here we present the role of two cellular entities, adrenergic neurons and virus-specific CD8+ T cells, in modulating antiviral NK cell responses. First, we provide evidence suggesting that cell-intrinsic adrenergic signaling is required for optimal adaptive NK cell responses. Early during mouse cytomegalovirus (MCMV) infection, NK cells up-regulated Adrb2 (which encodes the β2-adrenergic receptor), a process dependent on IL-12 and STAT4 signaling. NK cell–specific deletion of Adrb2 resulted in impaired NK cell expansion and memory during MCMV challenge, in part due to a diminished proliferative capacity. As a result, NK cell-intrinsic adrenergic signaling was required for protection against MCMV. Second, we show that the clonal expansion of NK cells is severely blunted in the absence of cytotoxic CD8+ T cells. This correlated with higher viral burden and an increased pro-inflammatory milieu, which maintained NK cells in a hyper- activated state. Antiviral therapy rescued NK cell expansion in the absence of CD8+ T cells, suggesting that high viral loads have detrimental effects on adaptive NK cell responses. Altogether, our data support a mechanism whereby cytotoxic innate and adaptive lymphocytes cooperate to ensure viral clearance and the establishment of robust clonal NK cell responses.