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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2019-01, Vol.68 (1), p.11-22
• Main Authors: Qiao, Guanxi, Bucsek, Mark J., Winder, Nicolette M., Chen, Minhui, Giridharan, Thejaswini, Olejniczak, Scott H., Hylander, Bonnie L., Repasky, Elizabeth A.
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Agonists - pharmacology; Adrenergic beta-Antagonists - pharmacology; Adrenergic receptors; Animals; Autonomic nervous system; Cancer Research; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cells, Cultured; Effector cells; Female; Glucose; Glucose - immunology; Glucose - metabolism; Glucose transporter; Glycolysis; Immune Tolerance - drug effects; Immune Tolerance - immunology; Immunological memory; Immunology; Immunosuppression; Isoproterenol; Isoproterenol - pharmacology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocytes T; Medicine; Medicine & Public Health; Memory cells; Metabolic rate; Metabolism; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Norepinephrine; Oncology; Original; Original Article; Propranolol; Propranolol - pharmacology; Receptors, Adrenergic, beta-2 - genetics; Receptors, Adrenergic, beta-2 - immunology; Receptors, Adrenergic, beta-2 - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; Sympathetic nerves; T cell receptors
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-018-2243-8

Primary and secondary lymphoid organs are heavily innervated by the autonomic nervous system. Norepinephrine, the primary neurotransmitter secreted by post-ganglionic sympathetic neurons, binds to and activates β-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 β2-adrenergic receptor (β2-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 β-AR agonist isoproterenol (ISO) was associated 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 was specifically dependent upon β2-AR, since it was not seen in adrb2 −/− CD8 + T-cells and was blocked by the β-AR antagonist propranolol. In addition, we found that mitochondrial function in CD8 + T-cells was also impaired by β2-AR signaling. This study demonstrates that one mechanism by which β2-AR signaling can inhibit CD8 + T-cell activation is 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.