A mechanism for immune regulation by the nervous system

A mechanism for immune regulation by the nervous system

Control of lymphocyte trafficking by adrenergic nerves

Nov 25, 2014

A group of researchers led by Kazuhiro SUZUKI (Associate Professor, Immunology Frontier Research Center (IFReC), Osaka University) revealed that β 2 -adrenergic receptors (β2 2 ARs) expressed on lymphocytes regulate their egress from lymph nodes by altering the responsiveness of chemokine receptors CCR7 and CXCR4. In mouse models of inflammation, signals through β 2 ARs were shown to inhibit trafficking of pathogenic lymphocytes and reduce their numbers recruited into inflamed tissues.

As the proverb “Illness starts in mind.” says, it has long been proposed that some aspects of immune responses are affected by activities of the nervous system. Indeed, lymphoid organs are innervated by various types of neurons and immune cells expressed corresponding neurotransmitter receptors. However, the cellular and molecular basis for neural regulation of immunity has been largely unknown. Adrenergic nerves transmit activities of the sympathetic nervous system to every organ system and play a major role in mediating stress responses. The group looked into how adrenergic nerves control the immune system, focusing on lymphocyte dynamics in the body.

This study demonstrated:

  1. 1. Adrenergic nerves contribute to the homeostasis of lymphocyte dynamics by regulating lymphocyte egress from lymph nodes through β 2 ARs expressed on lymphocytes.
  2. 2. There is a functional crosstalk between β 2 ARs and chemokine receptors CCR7 and CXCR4, by which inputs through β 2 ARs enhance responsiveness of these chemokine receptors to inhibit lymphocyte egress from lymph nodes.
  3. 3. In mouse models of inflammatory diseases, signals through β 2 ARs inhibit lymph node egress of pathogenic lymphocytes and prevent their migration to inflammatory sites, suggesting a mechanism for β 2 AR-mediated suppression of inflammation.

Collectively, the group revealed a molecular mechanism by which adrenergic nerves control lymphocyte dynamics in homeostatic and pathological conditions. This study implies how stress or emotional changes are reflected on immune functions through adrenergic nerves and provides a rationale for developing therapeutic strategies for immune disorders that control stress responses.

Figure. A model for adrenergic control of lymphocyte dynamics.


Lymphocyte recirculation through secondary lymphoid organs is essential for immunosurveillance and lymphocyte effector functions. In this study, we show that β2-adrenergic receptors (β2ARs) expressed on lymphocytes are involved in the regulation of lymphocyte dynamics by altering responsiveness of chemoattractant receptors. Agonist stimulation of lymphocyte β2ARs inhibited egress of lymphocytes from lymph nodes and rapidly produced lymphopenia in mice. Physiological inputs from adrenergic nerves contributed to retention of lymphocytes within lymph nodes and homeostasis of lymphocyte distribution among lymphoid organs. β2ARs physically interacted with chemokine receptors that promote lymphocyte retention in lymph nodes. Activation of β2ARs enhanced signals through the retention-promoting chemokine receptors and consequently inhibited lymphocyte egress from lymph nodes. In models of T-cell-mediated inflammatory diseases, stimulation of β2ARs inhibited egress of antigen-primed T cells from lymph nodes and reduced their recruitment into peripheral tissues, suggesting a mechanism for β2AR-mediated suppression of inflammatory responses. Thus, this study reveals a novel mechanism for controlling lymphocyte trafficking and provides additional insights into immune regulation by the nervous system.

To learn more about this research, please view the full research report entitled " Control of lymphocyte egress from lymph nodes through β2-adrenergic receptors " at this page of the Journal of Experimental Medicine website.

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