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Immune regulation by the nervous system
It has long been proposed that various aspects of immune responses are influenced by nervous system activity. Indeed, lymphoid organs are innervated by various types of neurons, and immune cells express neurotransmitter receptors to respond to the neural inputs. However, little is known about how the inputs from the nervous system control immune responses. To solve this problem, we are studying the cellular and molecular basis for the neural regulation of immunity. Adrenergic nerves constitute the efferent arc of the sympathetic nervous system and produce noradrenaline that induces cellular responses through α1-, α2-, β1-, β2- and β3-adrenergic receptors. Like other vital organs, lymphoid organs, including the bone marrow, thymus, spleen and lymph nodes, receive a rich supply of adrenergic nerves. We found that inputs from adrenergic nerves control lymphocyte egress from lymph nodes through β2-adrenergic receptors (J. Exp. Med. 2014, Fig. 1). Additionally, our study demonstrated that this mechanism helps generate a diurnal rhythm of adaptive immune responses in lymph nodes (J. Exp. Med. 2016).

Developing novel therapeutic strategies for inflammatory diseases
Lymphocyte migration is mediated by G protein-coupled receptors (GPCRs) that respond to chemoattractants, represented by chemokines. In search of novel factors involved in chemoattractant receptor signaling, we identified a protein complex consisting of copper metabolism MURR1 domain-containing (COMMD) 3 and COMMD8 (COMMD3/8 complex) (J. Exp. Med. 2019). The COMMD3/8 complex interacts with the C-terminal tail of chemoattractant receptors and promotes lymphocyte chemotaxis mediated by the receptors (Fig. 2). Deficiency of the COMMD3/8 complex severely impaired B cell migration in vivo and humoral immune responses. Therefore, the COMMD3/8 complex is essential for proper functioning of the immune system. Our recent data suggest that the COMMD3/8 complex may be involved in the pathogenesis of inflammatory diseases. Pharmacological inhibition of the COMMD3/8 complex may provide a novel approach for the treatment of the immune disorders.

Figure 1. Control of lymphocyte trafficking by adrenergic nerves
Activation of β2-adrenergic receptors expressed on lymphocytes enhances the responsiveness of CCR7 and CXCR4, chemokine receptors that promote lymph node retention of lymphocytes, and inhibits their egress from lymph nodes.

Figure 2. Role of the COMMD3/8 complex in chemoattractant receptor signaling
The COMMD3/8 complex functions as an adaptor that recruits GPCR kinase (GRK) 6 to chemoattractant receptors, promoting MAPK activation and consequently lymphocyte chemotaxis.