Abstract # 3159 Cytomegalovirus amplifies CD8 + T cell mobilization to psychological stress in humans, via a beta-adrenergic dependent mechanism linked to T-bet/Th1 effector cell differentiation

Psychological stress induces a beta-adrenergic dependent mobilization of CD8 + T lymphocytes (CTL) into the peripheral blood. Here we identified infection with Cytomegalovirus (CMV) as a major determinant of this mobilization, and characterized the cellular and transcriptional alterations that underlie enhanced responsivity. During acute stress (TSST), CMV-positive individuals (N = 35) demonstrated a 3-fold greater CTL mobilization compared to CMV-negative individuals (N = 48). Enhanced CTL mobilization was entirely confined to cells with an effector-memory phenotype (EMRA), which become markedly enriched in CMV-infected individuals. A beta-adrenergic receptor (beta-AR) dependent mechanism was confirmed by studies showing that stress-induced EMRA mobilization; (1) correlated with catecholamine release; (2) was completely abrogated by the beta-AR antagonist propranolol, and; (3) was reproduced by infusion of the beta-AR agonist isoproterenol. Micro-array analyses demonstrated selective 8-fold up-regulation of the beta2-AR gene (ADRB2) in EMRA as well as CMV-specific CTL. Longitudinal analyses confirmed that CMV-infection de novo induced rapid and lasting ADRB2 up-regulation in CTL, in conjunction with a Th1 T-bet/EOMES transcriptional profile. Subsequent studies in vitro replicated that functional beta2-AR expression increased with progressive CTL differentiation assessed as T-bet/Th1 expression. The present study identified a novel mechanism through which host–microbe interactions can regulate immune system responses to stress: CMV-infection induced T-bet differentiation accompanied by beta2-AR upregulation, which hereby enriched the CTL compartment with EMRA cells exhibiting an increased adrenergic sensitivity and enhanced mobilization during stress.