G-alpha-s-coupled receptor signaling controls circadian rhythm in integrin-mediated cell adhesion of virus-specific human CD8+ T cells

Abstract

Abstract Beta2-integrin activation in response to inside-out signaling by chemokines plays a major role in T-cell adhesion to the endothelium and the following extravasation into the inflamed tissue. We and others have previously shown that daytime increase in G-alpha-s-coupled receptor (GαsPCR) signaling, such as via beta2-adrenergic receptors counteracts integrin activation and promotes mobilization of effector CD8+ T cells from the marginal pool into the recirculation. In T cells, integrin activation is also rapidly induced by stimulation of antigen-specific T-cell receptors (TCR), resulting in the formation of stable immunological synapses. Therefore, we asked whether daytime increase in GαsPCR signaling inhibits integrin activation induced by TCR stimulation of human virus-specific T cells. Using ligand-complex-based adhesion assay to measure beta2-integrin activation, we show that affinity of integrins, which were activated by soluble cytomegalovirus virus peptide-major histocompatibility complex class I HLA-multimers is minimal during daytime. Additional in vitro experiments with GαsPCR agonists showed that epinephrine, norepinephrine, histamine, adenosine, and prostaglandins E2/D2 down-modulate the beta2-integrin activation; however, only epinephrine did so in physiological daytime concentrations, suggesting its mayor role in circadian regulation of T-cell adhesion. This active down-modulation of integrin activation through GαsPCR might be an essential mechanism of circadian immune defense regulation.