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. Therefore, we have been studying the cellular and molecular basis for the neural regulation of immunity since we set up our laboratory in 2011.

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 controlled lymphocyte egress from lymph nodes through β2-adrenergic receptors. Activation of β2-adrenergic receptors expressed on lymphocytes enhanced the responsiveness of CCR7 and CXCR4, chemokine receptors that promote lymph node retention of lymphocytes, and consequently inhibited lymph node egress of them (J. Exp. Med. 2014; Fig.1).

Figure 1

Figure 1. Adrenergic control of lymphocyte egress from lymph nodes

The activity of adrenergic nerves displays a circadian rhythm that is synchronized with the rest-activity cycle of the species. The noradrenaline release from adrenergic nerves increases during the daytime in humans, whereas it reaches a peak at night in rodents. We found that the night time surge of adrenergic nerve activity in mice restricted lymphocyte egress from lymph nodes, leading to an increase of lymphocyte numbers in lymph nodes. Immunization during the period of lymphocyte accumulation in lymph nodes enhanced antibody responses. The diurnal variation of the humoral immune response was dependent on adrenergic inputs and was diminished when lymphocyte recirculation through lymph nodes was stopped. These findings suggest that adrenergic control of lymphocyte trafficking contributes to daily fluctuations of adaptive immune responses (J. Exp. Med. 2016; Fig. 2).

Figure 2

Figure 2. Diurnal control of adaptive immunity by adrenergic nerves

Our study has revealed a part of the cellular and molecular basis by which adrenergic nerves control the immune system. At this moment, however, the mechanism for the crosstalk between β2-adrenergic receptors and chemokine receptors is unclear. Additionally, the real picture of the interaction between adrenergic nerves and lymphocytes remains to be visualized. We are going to address these questions in our future studies, and move a step closer to comprehensive understanding of immune regulation by the nervous system.