Lymphocyte called home: β2-adreneric neurotransmission confines T cells to lymph nodes to suppress inflammation.

The immune and nervous systems sense changes in the environment, mobilize host responses, and establish memories of threatening events. In this issue, an important study by Nakai et al. using experimental models of T cell inflammation shows that neurotransmission through β2-adrenergic signals in lymph nodes restricts T cell egress, thereby limiting potentially damaging tissue inflammation. This reveals a previously unrecognized neural mechanism for suppressing T cell mediated tissue damage.

Insight from Kevin Tracey

Like neurons, lymphocytes and other hematopoietic cells express neurotransmitter receptors. Ligand binding mediates intracellular signal transduction that modulates the expression of genes involved in immunological responses including cytokine production, cell proliferation and migration. Historically, immunology studies of neurotransmitter receptor signaling were descriptions of the biological effects of neurotransmitter receptor signaling on immune responses, regardless of the neurotransmitter’s cell of origin. Recent convergence of neurophysiology and immunology, however, has delineated the maps of specific neural circuits that regulate immunity. Elucidation of these genetic and molecular mechanisms has significant implications for understanding innate and adaptive immunity.

It has been known for decades that adrenergic neurons innervate lymph nodes. Missing was the answer to how such neurons might regulate T lymphocytes. In the present study, ablation of adrenergic signaling to lymph nodes, or deletion of β2-adrenergic receptors from lymphocytes resulted in lymphopenia in lymph nodes. β2-adrenergic receptors physically associated with CCR7 and CXCR4, which control lymphocyte retention in lymph nodes, resulting in prolonged RAC1 signaling. CCR7 and CXCR4 signals enhanced lymph node retention of B and T cells, respectively. Moreover, activation of β-adrenergic signals inhibited lymph node transit of antigen-primed T cells, significantly curtailing the development of paralysis in EAE and attenuating inflammation in DTH. This indicates that β2-adrenergic neural signaling can override T cell damage to tissues.

Adrenergic signals via β2-adrenergic receptor (β2AR) in T cells lead to the formation of heteromeric protein complexes of β2AR with CCR7 and CXCR4. This culminates in increased adhesion to lymph node stroma and T cell retention.

Immunity cannot be fully understood without understanding the neural circuits that reflexively modulate it. The growing list of reflexive neural circuits that specifically influence immunity provides an understanding of distinct molecular and neurophysiological mechanisms that inhibit and stimulate immunity. These circuits operate reflexively, meaning that sensory input stimulates the outgoing, efferent arc of the circuit to regulate immunity. The incoming signals can be activated by cytokines, products of tissue injury, and even by bacterial products directly. The innate immune system is thus not alone on the front line against infection and injury; this role is shared with sensory neurons. Closed feedback loops through these neural circuits can exert significant influence on the development of innate and adaptive immunity.

So, if the question being studied is “what is the basis of immunity and how is it controlled?”, then it is time to face up to the answers provided by studies of neural circuits that reflexively control immune responses. Nearly every cell of the body is within signaling range of sensory neurons capable of monitoring their biochemical, metabolic, and physical states. And all of the major organs of the immune system are targeted by neurons that can in turn transmit reflexive neural signals.

The challenge for immunologists today is to delineate specific neural circuit mechanisms regulating specific aspects of immunity. In the 20th century, Charles Sherrington taught that the nervous system is built upon single units of reflex action; the time has arrived to apply these principles to immunology. This represents a major advance over studies of generalized neurotransmitter responses to hematopoietic cells. Mapping specific input and output neural circuits has opened new insights into understanding immunity and holds significant opportunity for learning how to therapeutically modulate it.