The overall goal of this application is to evaluate and define the bi- directional signaling between epidermal Langerhans cells (LC) and nerves This work is based on the following observations made in the initial funding period: (1) LC are anatomically-associated with calcitonin gene-related peptide (CGRP)-containing nerves, (2) CGRP regulates LC function, (3) LC express receptors for several other neuropeptides, as well as beta-adrenergic receptors, and some of these agonists regulate aspects of LC function including cytokine expression and antigen presenting function, and (4) LC are capable of producing neurotrophins. Thus, we hypothesize that bidirectional signaling occurs between nerves and LC with nerves influencing LC by production of neuron-derived signals while LC influence nerve cells by production of neurotrophins. This signaling allows regulation of immune function by neurons and may promote the formulation of the close association between nerves and LC that promotes this functional regulation. In Aim 1, we will test this hypothesis by examining LC for responses to neuropeptides and neuro-transmitters (effects on cytokine expression, co- stimulatory molecule expression and antigen presentation) and production of neurotrophins. Complementary in vivo experiments will test the physiological importance of neuropeptides and neurotransmitters in both induction and elicitation of immunity. Cytokine-deficient ("knock-out") mice will be used to test the involvement of certain cytokines in neural factor effects. In Aim 2, we will study the influence of primary neurons and neuropeptides on the migration of LC cells. Conversely, we will study the factors released by nerve cells that induce migration of LC towards nerve cells. The proposed studies will define an important locus of interaction between the nervous system and the immune system. The results obtained may provide a greater understanding of how the nervous system influences immunity within the skin, and how the association between the neural and immune systems in the skin is formed. These studies may lead to currently unforseen new therapeutic approaches to treat immunologic derangements, ranging form psoriasis to skin cancer.