title: Targeting ß2 adrenergic receptors regulate human T cell function directly and indirectly.
abstract: It is well-established that central nervous system activation affects peripheral blood mononuclear cell (PBMCs) function through the release of the catecholamines (Epi) and norepinephrine (NE), which act on ß2-adrenergic receptors (ß2AR). However, most studies have used non-specific stimulation of cells rather than antigen-specific responses. Likewise, few studies have parsed out the direct effects of ß2AR stimulation on T cells versus indirect effects via adrenergic stimulation of antigen presenting cells (APC). Here we report the effect of salmeterol (Sal), a selective ß2AR agonist, on IFN-γ(+) CD4 and IFN-γ(+) CD8 T cells following stimulation with Cytomegalovirus lysate (CMVL-strain AD169) or individual peptides spanning the entire region of the HCMV pp65 protein (pp65). Cells were also stimulated with Staphylococcal enterotoxin B. Additionally, we investigated the effect of Epi and Sal on cytotoxic cell killing of transfected target cells at the single cell level using the CD107a assay. The results show that Sal reduced the percentage of IFN-γ(+) CD4 and IFN-γ(+) CD8 T cells both when applied directly to isolated T cells, and indirectly via treatment of APC. These inhibitory effects were mediated via a ß2 adrenergic-dependent pathway and were stronger for CD8 as compared to CD4 T cells. Similarly, the results show that Sal suppressed cytotoxicity of both CD8 T and NK cells in vitro following stimulation with Chinese hamster ovary cell line transfected with MICA(*009) (T-CHO) and the human erythromyeloblastoid leukemic (K562) cell line. The inhibitory effect on cytotoxicity following stimulation with T-CHO was stronger in NK cells compared with CD8 T cells. Thus, targeting the ß2AR on lymphocytes and on APC leads to inhibition of inflammatory cytokine production and target cell killing. Moreover, there is a hierarchy of responses, with CD8 T cells and NK cells inhibited more effectively than CD4 T cells.
authors.affiliation: School of Sports and Exercise, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: a.zalli@ucl.ac.uk.
authors.forename: A
authors.initials: A
authors.lastname: Zalli
authors.affiliation: Department of Psychology, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: j.a.bosch@uva.nl.
authors.forename: J A
authors.initials: JA
authors.lastname: Bosch
authors.affiliation: School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: O
authors.initials: O
authors.lastname: Goodyear
authors.affiliation: School of Sports and Exercise, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: N
authors.initials: N
authors.lastname: Riddell
authors.affiliation: School of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: H M
authors.initials: HM
authors.lastname: McGettrick
authors.affiliation: School of Cancer Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: P
authors.initials: P
authors.lastname: Moss
authors.affiliation: School of Immunity and Infection, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: g.r.wallace@bham.ac.uk.
authors.forename: G R
authors.initials: GR
authors.lastname: Wallace
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000276:immunology; D016466:CHO Cells; D003412:Cricetulus; D003587:Cytomegalovirus / Q000276:immunology; D004768:Enterotoxins / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D010750:Phosphoproteins / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000494:pharmacology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D004768:Enterotoxins; D010750:Phosphoproteins; D018343:Receptors, Adrenergic, beta-2; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; C031818:enterotoxin B, staphylococcal; D000068299:Salmeterol Xinafoate; D007371:Interferon-gamma; D000420:Albuterol; D004837:Epinephrine
keywords: Adrenergic agonists; Catecholamines; Immune function; Lymphocytosis; Sympathetic nervous system