PROJECT SUMMARY This application seeks to understand how circadian rhythms control T cell immunity to influenza infection through signals delivered by the sympathetic nervous system. Circadian rhythms are biological clocks that are entrained by light/dark cycles, and in mammals, those rhythms are synchronized systemically throughout the body via signals delivered by sympathetic and parasympathetic neurons. Our recent studies uncovered an unexpected role for the β2-adrenergic receptor in cytolytic responses of CD8+ T cells to a virus infection. Further, we found that selective deletion of the Adrb2 on CD8+ T cells profoundly disrupted circadian gene expression and oscillation frequencies as a function of light/dark entrainment. This proposal will test the hypothesis that the signaling through the ADRB2 in CD8+ T cells regulates circadian rhythm genes, and that those genes are required for orchestrated T cell responses to influenza infection. Aim 1 will distinguish the roles of the Adrb2 and downstream core clock in CD8-mediated lung inflammation during influenza infection. Aim 2 will determine how jet-lag impacts CD8+ T cell responses to influenza. This proposal tests a very straight- forward hypothesis, which if supported, will be the first to connect a circadian rhythm entrainment receptor to downstream T cells responses to influenza. The outcomes of this research will significantly advance our understanding of environmental pathways that regulate immune responses to influenza and improve mouse models of viral pathogenesis and vaccine design.