Adrenergic signaling impairs activation of CD8+ T cells by blocking metabolic reprogramming

Abstract

Abstract Adrenergic stress promotes tumor progression by several mechanisms. Mice housed at standard housing temperature (ST, 22°C) experience chronic adrenergic cold stress sufficient to elevate norepinephrine levels compared to mice housed at thermoneutrality (TT, 30°C) and we found that tumors grow faster at ST. We have also previously reported that the anti-tumor immune response is suppressed at ST. Tumor infiltrating CD8+ T cells from these mice have reduced expression of activation and effector function markers. These deficits are reversed by housing mice at TT which reduced adrenergic stress or by treating mice at ST with the β-adrenergic receptor antagonist propranolol. Coincident with this effect, we see increased cell surface expression of the glucose transporter-1 on CD8+ T cells, which is critical for glycolysis. Based on the fact that T cell activation and function require up-regulation of glycolysis (i.e. “metabolic reprogramming”), we hypothesize that adrenergic signaling impairs the antitumor efficacy of CD8+ T cells by impairing metabolic reprogramming. To test this hypothesis, CD8+ T cells were isolated and activated and treated +/− the β-AR agonist isoproterenol (ISO). Using Seahorse Extracellular Flux Analysis to compare the bioenergetics of control and ISO treated CD8+ T cells, we found that adrenergic signaling significantly reduced ECAR (glycolysis) and increased the ratio of oxidative phosphorylation/glycolytic rate (OCR/ECAR). These data support the idea that adrenergic signaling blocks metabolic reprogramming in CD8+ T cells thereby inhibiting T cell activation. Current work is focused on identifying the precise intracellular pathways by which adrenergic signaling and T cell metabolism intersect.