PROJECT SUMMARY – ABSTRACT This application seeks to understand how circadian rhythms control immune function 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 sympathetic nervous system in the generation and development of memory CD8+ T cells in response to a virus infection. CD8+ T cells lacking the b2-adrenergic receptor (ADRB2) expanded and developed into primary effectors during early responses to virus, but their progeny failed to develop into a stable pool of memory cells. This defect correlated with a profound dysregulation of genes involved in circadian rhythms during the early stages of T cell priming. 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 memory T cell development. Aim 1 will measure the periodic oscillations of core clock gene and protein expression in the absence or presence of the Adrb2 in CD8+ T cells. Aim 2 will determine the intrinsic role of clock genes in regulating memory CD8+ T cell development. This proposal tests a very straight-forward hypothesis, which if supported, will be the first demonstration that immunologic memory is controlled by the sympathetic nervous system through circadian rhythms. The implications of such a discovery will have a far-reaching impact on infectious diseases, vaccination, and cancer immunotherapy.