Sympathetic neural signaling via the β2‐adrenergic receptor suppresses T‐cell receptor‐mediated human and mouse CD8⁺ T‐cell effector function

Abstract

Post-ganglionic sympathetic neurons innervate secondary lymphoid organs and secrete norepinephrine (NE) as the primary neurotransmitter. NE binds and signals through 5 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 CTL 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.

β-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

“…NE signaling through β 2 -ARs on lymphocytes has recently been shown to suppress immune cell function in non-oncological settings (17,23,24), therefore we asked whether this signaling pathway mediates immune suppression in mice housed at 22°C. We repeated the experiments shown above (Fig.…”

“…As they point out, NE signaling through β-ARs on CD4 + lymphocytes induces production of the T H 2 cytokines IL-6 and IL-10 suppressing production of the T H 1 cytokines IL-12, TNF-α and INF-γ thereby reducing the generation of cytotoxic CD8 + T cells. Recently, Estrada et al, investigated adrenergic signaling specifically in CD8 + T cells and found that β 2 -AR activation decreased IFN-γ, TNF-α, and IL-2 production and suppressed the ability of CD8 + T cells to kill virally infected cells (24). …”

“…Igh-1b Icr Tac Prkdc scid (SCID) mice from the Laboratory Animal Resource at RPCI. BALB/c mice globally deficient in β 2 -ARs ( Adrb2 −/− ) were provided by David Farrar (University of Texas Southwestern Medical Center) (24). OT-1 (B6.129S7-Rag1tm1Mom Tg[TcraTcrb]1,100Mjb) mice were provided by Dr. Minhyung Kim (RPCI).…”

“…Grebe et al (23) have shown that anti-influenza CD8 + T cell responses in vivo are limited by adrenergic signaling, and Estrada et al (24) clearly demonstrate suppression of effector function by β 2 -AR signaling in both human and mouse CD8 + T cells. These studies support the idea that adrenegic signaling could suppress anti-tumor immunity, however, the impact of adrenergic stress on the development of anti-tumor immunity, the immune contexture of tumors, or the role that β-AR signaling may have in dictating the sensitivity or resistance of tumors to checkpoint inhibitor therapy has received virtually no attention.…”

“…Here, using the pan-β-AR blocker propranolol, as well as β 2 -AR receptor knockout mice ( Adrb2 −/− ) in which the immune cells are non-responsive to adrenergic signaling (24), we report for the first time that the mechanism mediating differences in tumor growth and the anti-tumor immune response observed between mice housed at 22°C and 30°C, are dependent upon β-AR signaling. Furthermore, reducing β-AR signaling either by housing mice at 30°C or by treating mice at 22°C with propranolol, we discovered that we could “reset” the baseline immune response in murine tumor models and significantly improve responses to anti-PD-1 checkpoint blockade therapy.…”