title: Sympathetic neural signaling via the β2-adrenergic receptor suppresses T-cell receptor-mediated human and mouse CD8(+) T-cell effector function.
abstract: Postganglionic sympathetic neurons innervate secondary lymphoid organs and secrete norepinephrine (NE) as the primary neurotransmitter. NE binds and signals through five distinct members of the adrenergic receptor family. In this study, we show elevated expression of the β2-adrenergic receptor (ADRB2) on primary human CD8(+) effector memory T cells. Treatment of both human and murine CD8(+) T cells with NE decreased IFN-γ and TNF-α secretion and suppressed their cytolytic capacity in response to T-cell receptor (TCR) activation. The effects of NE were specifically reversed by β2-specific antagonists. Adrb2(-/-) CD8(+) T cells were completely resistant to the effects of NE. Further, the ADRB2-specific pharmacological ligand, albuterol, significantly suppressed effector functions in both human and mouse CD8(+) T cells. While both TCR activation and stimulation with IL-12 + IL-18 were able to induce inflammatory cytokine secretion, NE failed to suppress IFN-γ secretion in response to IL-12 + IL18. Finally, the long-acting ADRB2-specific agonist, salmeterol, markedly reduced the cytokine secretion capacity of CD8(+) T cells in response to infection with vesicular stomatitis virus. This study reveals a novel intrinsic role for ADRB2 signaling in CD8(+) T-cell function and underscores the novel role this pathway plays in adaptive T-cell responses to infection.
authors.affiliation: Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Leonardo D
authors.initials: LD
authors.lastname: Estrada
authors.affiliation: Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Didem
authors.initials: D
authors.lastname: Ağaç
authors.affiliation: Department of Immunology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Farrar
mesh_terms: D056704:Adaptive Immunity; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage*; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D016207:Cytokines / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000008:administration & dosage*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D000068299:Salmeterol Xinafoate / Q000008:administration & dosage; D015398:Signal Transduction
chemical_list: D000316:Adrenergic alpha-Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D016207:Cytokines; D018343:Receptors, Adrenergic, beta-2; D011948:Receptors, Antigen, T-Cell; D000068299:Salmeterol Xinafoate; D009638:Norepinephrine
keywords: CD8+ T cells; Cytokine; Cytolysis; Norepinephrine; β2-Adrenergic receptor