Defining the interaction between adrenergic nerves and immune memory - PROJECT SUMMARY The nervous and immune systems interact to influence one another, however our understanding of this interaction and how it affects protection from infection is incomplete. Patients with peripheral nerve damage are highly susceptible to frequent, severe infections, indicating some underlying immunodeficiency. Lymph nodes contain adrenergic nerves that innervate the T cell areas and reticulin fiber structures called trabeculae; both T cells and the stromal cells that form trabeculae express receptors for the adrenergic neurotransmitter norepinephrine. We have found that adrenergic nerves are necessary for the generation of CD4 T cell memory after Staphylococcus aureus infection or vaccination. These nerves are also critical for remodeling of trabeculae after infection or vaccination, impacting the permeability of the lymph node to large soluble antigens. Significantly, the B cell response to large antigens was impaired by nerve depletion, while the B cell response to small antigens was not impacted. Both CD4 T cell memory and effective B cell responses are critical in protection from infection. We hypothesize that adrenergic nerves in the lymph node communicate directly with both T cells and stromal cells to promote adaptive immune responses. This hypothesis will be rigorously tested at multiple levels to determine the mechanism by which nerves promote CD4 T cell memory, germinal centers, and trabeculae remodeling during immune responses. We will interrogate whether direct signaling by adrenergic nerves to T cells promotes CD4 T cell memory, whether direct signaling to stromal cells drives remodeling in the lymph node, and whether large antigens require these remodeled areas to gain access to the lymph node. We will investigate how nerves promote formation of highly proliferative CD4 memory cells, with a focus on the central memory transcriptional program and functions critical for memory cell expansion. We will also evaluate whether nerves influence the differentiation of CD4 T cells, and if this is mediated in part through metabolic reprogramming of the cells. We will determine whether these effects are due to direct signaling from the nerves to the T cells, or if nerves act on antigen presenting cells to promote memory. We will measure what transcriptional changes occur in stromal cells in response to adrenergic nerve signaling both in vivo and in vitro. Finally we test whether this remodeling occurs to allow large antigens entry into the lymph node to drive B cell responses. These studies will fill a critical knowledge gap regarding the function of the nervous system in the lymph node during immune responses. A better understanding of how the nervous and immune system intersect to defend against infection will impact human health in numerous ways, including better vaccine design and better treatment options for patients with peripheral nervous system dysfunction, a patient group with notable susceptibility to opportunistic infections.
