β2-Adrenoreceptor Agonist Inhibits Antigen Cross-Presentation by Dendritic Cells

Abstract

Despite widespread usage of β-adrenergic receptor (AR) agonists and antagonists in current clinical practice, our understanding of their interactions with the immune system is surprisingly sparse. Among the AR expressed by dendritic cells (DC), β2-AR can modify in vitro cytokine release upon stimulation. Because DC play a pivotal role in CD8+ T cell immune responses, we examined the effects of β2-AR stimulation on MHC class I exogenous peptide presentation and cross-presentation capacities. We demonstrate that β2-AR agonist-exposed mature DC display a reduced ability to cross-present protein Ags while retaining their exogenous peptide presentation capability. This effect is mediated through the nonclassical inhibitory G (Gαi/0) protein. Moreover, inhibition of cross-presentation is neither due to reduced costimulatory molecule expression nor Ag uptake, but rather to impaired phagosomal Ag degradation. We observed a crosstalk between the TLR4 and β2-AR transduction pathways at the NF-κB level. In vivo, β2-AR agonist treatment of mice inhibits Ag protein cross-presentation to CD8+ T cells but preserves their exogenous MHC class I peptide presentation capability. These findings may explain some side effects on the immune system associated with stress or β-agonist treatment and pave the way for the development of new immunomodulatory strategies.

Norepinephrine Controls Effector T Cell Differentiation through β2-Adrenergic Receptor–Mediated Inhibition of NF-κB and AP-1 in Dendritic Cells

“…Based on our own data (Fig. 4A, 4B) and previous studies (14,15) showing that NE and b 2 AR agonists increase IL-10 production by LPS-DC, we examined whether b 2 ARmediated downregulation of IL-12p70 production by LPS-DC results from increased IL-10 release. Using iDC generated from IL-10 2/2 mice, we found that IL-10 deficiency does not affect b 2 AR-mediated inhibition of LPS-induced IL-12p70 production in DC (Fig.…”

“…It is known that stimulation of different adrenergic receptors expressed by DC modifies their migration capabilities (11), cytokine secretion (12)(13)(14), Ag uptake (15), and ability to perform cross-presentation (14). Specifically with regard to cytokine secretion, it was shown that stimulation of b 2 -adrenergic receptor (b 2 AR) modulates cytokine production by activated DC, primarily by inhibiting some proinflammatory cytokines, such as TNF-a, IL-12, and IL-6, and by increasing IL-10 and IL-33 release by these cells (13,14,16).…”

“…It is known that stimulation of different adrenergic receptors expressed by DC modifies their migration capabilities (11), cytokine secretion (12)(13)(14), Ag uptake (15), and ability to perform cross-presentation (14). Specifically with regard to cytokine secretion, it was shown that stimulation of b 2 -adrenergic receptor (b 2 AR) modulates cytokine production by activated DC, primarily by inhibiting some proinflammatory cytokines, such as TNF-a, IL-12, and IL-6, and by increasing IL-10 and IL-33 release by these cells (13,14,16). Although previous studies showed that b 2 AR agonists impair the ability of LPS-activated DC to promote Th1 differentiation, favoring instead the generation of Th2 cells (17), Th17 cells, and induced Foxp3 + T cells (18,19), our understanding of how b 2 AR stimulation can impact DCdriven naive CD4 + T cell differentiation remains limited.…”

Antigen Presentation After Stroke

“…Most features of the stroke-induced immunodepression may favor tolerogenic immune responses. Thus, catecholamines can inhibit the antigen-presenting capability via β2-adrenoceptors [135][136][137], corticosteroids inhibit the production of inflammatory cytokines in APCs and induce the development of tolerogenic APCs [138,139], and glucocorticoid-stimulated monocytes reduce the release of interferon-γ and IL-17 in lymphocytes, favoring the generation of Tregs [140]. IL-10 also inhibits autoimmune reactions acting on several immune cells, including APCs inducing anergic T cells that are able to suppress activation, and function of T cells in an antigen-specific manner [141].…”

Immunopathogenetic Aspects of Ischemic Stroke

“…Действительно, у пациентов с инсультом выявляется повышенный уровень в сыворотке крови кортизола и катехоламинов, высокая концентрация которых является пре-диктором летального исхода [3,16]. Взаимодей-ствуя с β2-адренорецепторами, катехоламины подавляют антигенпрезентирующую функцию дендритных клеток и моноцитов; индуцируют толерогенные дендритные клетки, способные вызывать анергию Т-лимфоцитов и генерацию Тreg [44]. Активированные глюкокортикоидами моноциты подавляют в Т-клетках продукцию IFNγ и IL-17 и также индуцируют генерацию Тreg [126].…”