β-Adrenergic signaling blocks murine CD8+ T-cell metabolic reprogramming during activation: a mechanism for immunosuppression by adrenergic stress

Primary and secondary lymphoid organs are heavily innervated by the autonomic nervous system. Norepinephrine, the primary neurotransmitter secreted by post-ganglionic sympathetic neurons, binds toand activates -adrenergic receptors expressed on the surface of immune cells and regulates the functions of these cells. While it is known that both activated and memory CD8(+) T-cells primarily express the 2-adrenergic receptor (2-AR) and that signaling through this receptor can inhibit CD8(+) T-cell effector function, the mechanism(s) underlying this suppression is not understood. Under normal activation conditions, T-cells increase glucose uptake and undergo metabolic reprogramming. In this study, we show that treatment of murine CD8(+) T-cells with the pan -AR agonist isoproterenol (ISO) wasassociated with a reduced expression of glucose transporter 1 following activation, as well as decreased glucose uptake and glycolysis compared to CD8(+) T-cells activated in the absence of ISO. The effect of ISO wasspecifically dependent upon 2-AR, since it was not seen in adrb2(-/-) CD8(+) T-cells and wasblocked by the -AR antagonist propranolol. In addition, we found that mitochondrial function in CD8(+) T-cells was also impaired by 2-AR signaling. This study demonstrates that one mechanism by which 2-AR signaling can inhibit CD8(+) T-cell activationis by suppressing the required metabolic reprogramming events which accompany activation of these immune cells and thus reveals a new mechanism by which adrenergic stress can suppress the effector activity of immune cells.