Beta2-adrenergic receptor (B2AR) signaling is known to impairKeywords: Foxp3 · Noradrenaline · Sympathetic nervous system · Treg cell Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionLymphoid organs such as the spleen and the lymph nodes are richly innervated by the sympathetic nervous system (SNS), especially within T-cell areas [1]. Immune responses can be moduCorrespondence: Dr. Alexandre S. Basso e-mail: asbasso@unifesp.br lated by catecholamines released upon sympathetic activity only if immune cells are able to respond to them by expressing functional catecholaminergic receptors. Indeed, the beta2-adrenergic receptor (B2AR) has been described as the main adrenergic receptor expressed in immune cells, including dendritic cells, macrophages, CD4 + T cells, CD8 + T cells, and B cells [2,3]. Furthermore, increased noradrenaline release in the spleen followed by the activation of antigen-specific T and B cells has been already reported, indicating that an adaptive immune response can lead to enhanced SNS activity within lymphoid organs [4]. Taken 1002 Marcia. G. Guereschi et al. Eur. J. Immunol. 2013. 43: 1001-1012 sympathetic innervation of lymphoid organs, SNS activation due to adaptive immune responses, and the expression of adrenergic receptors by immune cells build a solid case supporting the concept that the SNS represents a feedback mechanism that is able to modulate immune responses [5]. Thus far, it has been shown that B2AR is expressed in CD4 + naïve T cells and Th1 clones while it is completely absent in Th2 clones [3,6]. CD4 + T-cell stimulation along with B2AR activation decreased IL-2 production and IL-2 receptor α-chain (CD25) expression in a cAMP-dependent way [3,[6][7][8]. Activation of Th1 clones in the presence of a B2AR agonist may also impair IL-2 and IFN-γ expression [6,7]. Furthermore, by selective inhibition of IL-12 production in LPS-stimulated human dendritic cells, B2AR agonists were found to block in vitro differentiation of neonatal CD4 + T cells into IFN-γ-producing cells, favoring IL-4 production instead [9]. Therefore information on SNS-mediated modulation of CD4 + T-cell immune responses via B2AR activation has been concentrated on the dichotomy Th1/Th2; and in general these data point to a role for B2AR activation in inhibiting the development of Th1 responses [6,8,9]. Very little is known on how adrenergic neurotransmitters could modulate the activity of other CD4 + T-cell subsets, among them Foxp3− T cells possess transcripts for the beta1-adrenergic receptor (B1AR) and the alpha2A-adrenergic receptor (A2aAR), besides the B2AR (Supporting Information Fig. 1A). Among those three, the B2AR is far more expressed than the other two (Supporting Information Fig. 1A). that Treg cells also express the B2AR, the B1AR, and the A2aAR (Supporting Information Fig. 1B). In Treg cells, B2AR was also expressed at higher levels as compared to B1AR and A2aAR (Supporting Information Fig. 1B). When comparing B2AR mRN...

Despite accumulating evidence indicating that neurotransmitters released by the sympathetic nervous system can modulate the activity of innate immune cells, we still know very little about how norepinephrine impacts signaling pathways in dendritic cells (DC) and the consequence of that in DC-driven T cell differentiation. In this article, we demonstrate that β2-adrenergic receptor (β2AR) activation in LPS-stimulated DC does not impair their ability to promote T cell proliferation; however, it diminishes IL-12p70 secretion, leading to a shift in the IL-12p70/IL-23 ratio. Although β2AR stimulation in DC induces protein kinase A–dependent cAMP-responsive element–binding protein phosphorylation, the effect of changing the profile of cytokines produced upon LPS challenge occurs in a protein kinase A–independent manner and, rather, is associated with inhibition of the NF-κB and AP-1 signaling pathways. Moreover, as a consequence of the inverted IL-12p70/IL-23 ratio following β2AR stimulation, LPS-stimulated DC promoted the generation of CD4+ T cells that, upon TCR engagement, produced lower amounts of IFN-γ and higher levels of IL-17. These findings provide new insights into molecular and cellular mechanisms by which β2AR stimulation in murine DC can influence the generation of adaptive immune responses and may explain some aspects of how sympathetic nervous system activity can modulate immune function.

We have previously shown that regulatory T (Treg) cells that accumulate in the airways of allergic mice upregulate CC-chemokine receptor 4 (CCR4) expression. These Treg cells suppressed in vitro Th2 cell proliferation but not type 2 cytokine production. In the current study, using a well-established murine model of allergic lung disease or oral tolerance, we evaluated the in vivo activity of Treg cells in allergic airway inflammation with special focus on CCR4 function. We found that allergic, but not tolerant, mice treated with anti-CD25 Ab showed increased airway eosinophilia and IL-5– or IL-4–producing Th2 cells when compared with untreated mice. Notably, mice with CCR4 deficiency displayed an augmented airway allergic inflammation compared with wild-type or CCR2 knockout (KO) mice. The allergic phenotype of CCR4KO mice was similar to that observed in anti-CD25–treated mice. The exacerbated allergic inflammation of CCR4KO mice was directly associated with an impaired migration of Treg cells to airways and augmented frequency of pulmonary Th2 cells. Adoptive transfer of CD25+CD4+ T cells expressing high levels of CCR4, but not CCR4KO CD25+CD4+ T cells, attenuated the severe airway Th2 response of CCR4KO mice. Our results show that CCR4 is critically involved in the migration of Treg cells to allergic lungs that, in turn, attenuate airway Th2 activation and allergic eosinophilic inflammation.

Highlights d Sympathetic nervous system (SNS) limits CNS autoimmune inflammation d Adrb2 signaling in immune cells mediates the SNS effects on EAE development d Adrb2-mediated SNS suppressive effects involve ICERdriven inhibition of CD4 + T cells

Dendritic cells are of paramount importance bridging innate and adaptive immune responses. Depending on the context, after sensing environmental antigens, commensal microorganisms, pathogenic agents, or antigens from the diet, dendritic cells may drive either different effector adaptive immune responses or tolerance, avoiding tissue damage. Although the plasticity of the immune response and the capacity to regulate itself are considered essential to orchestrate appropriate physiological responses, it is known that the nervous system plays a relevant role controlling immune cell function. Dendritic cells present in the skin, the intestine, and lymphoid organs, besides expressing adrenergic receptors, can be reached by neurotransmitters released by sympathetic fibers innervating these tissues. These review focus on how neurotransmitters from the sympathetic nervous system can modulate dendritic cell function and how this may impact the immune response and immune-mediated disorders.