ß-Adrenergic signaling blocks murine CD8+ T-cell metabolic reprogramming during activation: a mechanism for immunosuppression by adrenergic stress.
Cancer Immunol Immunother
; 68(1): 11-22, 2019 Jan.
Article
em En
| MEDLINE
| ID: mdl-30229289
ABSTRACT
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 ß-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 ß2-adrenergic receptor (ß2-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 ß-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 ß2-AR, since it was not seen in adrb2-/- CD8+ T-cells and was blocked by the ß-AR antagonist propranolol. In addition, we found that mitochondrial function in CD8+ T-cells was also impaired by ß2-AR signaling. This study demonstrates that one mechanism by which ß2-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.
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MEDLINE
Assunto principal:
Ativação Linfocitária
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Transdução de Sinais
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Receptores Adrenérgicos beta 2
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Linfócitos T CD8-Positivos
Limite:
Animals
Idioma:
En
Revista:
Cancer Immunol Immunother
Ano de publicação:
2019
Tipo de documento:
Article