The β₂-adrenergic receptor (<i>Adrb2</i>) entrains circadian gene oscillation and CD8⁺ T cell differentiation in response to virus infection.

Abstract

Adaptive immune cells are regulated by circadian rhythms both under steady state conditions and during responses to infection. Cytolytic CD8⁺ T cells display variable responses to infection depending upon the time of day of exposure. However, the neuronal signals that entrain these cyclic behaviors remain unknown. Immune cells express various neurotransmitter receptors, and we demonstrate that selective deletion of the β₂-adrenergic receptor (<i>Adrb2</i>) gene perturbs the normal diurnal oscillation of clock gene expression in CD8⁺ T cells, such as <i>Per2</i> and <i>Bmal1</i>. Consequently, their time-of-day-dependent response to vesicular stomatitis virus was dysregulated, and the diurnal development of CD8⁺ T cells into variegated populations of memory/effectors was altered in the absence of ADRB2 signaling. The diurnal fluctuations in T cell phenotypes were a distinct developmental process, independent of migration kinetics within the spleen. Thus, <i>Adrb2</i> directly entrains core clock gene oscillation and regulates T cell developmental responses to virus infection as a function of time of day of pathogen exposure.