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Detailed microscopy studies have revealed abundant innervation of the lymph node parenchyma, with specific innervation targeting single antigen-presenting cells ( 2). Lymph nodes are also richly innervated by both afferent and efferent nerve fibers. Controlling the lymphatic transit of antigens to these draining lymph nodes is essential to mount an efficient host defense against pathogens, and is subject to several regulatory mechanisms, including the nervous system.Ī dense plexus of neural fibers is present in blood vessels and the surrounding periarterial lymphatic sheath in lymph nodes ( 1). Antigen-specific T and B cells are primed and activated in the draining lymph nodes, resulting in antigen-specific acute and memory responses. Antigens are transported to the local lymph nodes, processed by antigen-presenting cells and presented to lymphocytes to trigger an immune response. These lymphoid organs play an essential role in peripheral inflammatory responses to immunological challenge and/or tissue injury. The nervous system communicates with the immune system via direct innervation of primary and secondary lymphoid organs. The immune and nervous systems coevolved under the threat of environmental dangers and work in concert to sense changes in the environment, mobilize host responses and establish memories of threatening events. Together, these studies reveal that neuronal circuits modulate antigen trafficking through a pathway that requires Na V1.8 and FcγR. Colocalization of PGP9.5-expressing neurons, FcγRI receptors and labeled antigen occurs at the antigen challenge site. Genetic deletion of FcγRI/FcεRI also reverses the antigen restriction. Ablating Na V1.8 + sensory neurons significantly reduces antigen restriction in immunized mice. In contrast, neural activation using magnetic stimulation significantly decreases antigen trafficking in naïve animals as compared with sham controls. Administering bupivacaine into the lymph node region restores antigen flow in immunized animals. Re-exposure to KLH in previously immunized mice leads to decreased flow from the popliteal to the sciatic lymph node as compared with naïve mice. The antigen keyhole-limpet hemocyanin (KLH) injected into the mouse hind paw flows from the popliteal lymph node to the sciatic lymph node, continuing through the upper lymphatics to reach the systemic circulation. Here we describe the role of neurons in sensing and restricting antigen flow in lymph nodes. In previously immunized animals, antigens become trapped in the draining lymph nodes, but the underlying mechanism that controls antigen restriction is poorly understood. When pathogens and toxins breech the epithelial barrier, antigens are transported by the lymphatic system to lymph nodes.