Spleen glia in autonomic regulation of immunity

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Project Summary. Stress strongly influences the immune system, particularly antigen-specific adaptive immune responses, via sympathetic outflow and activation of adrenergic receptors. However, although there are consistent findings that the sympathetic neurotransmitters epinephrine and norepinephrine regulate antigen presenting cells and T and B lymphocytes via adrenergic receptors, the results are context dependent–either activation or suppression of antigen-dependent responses is observed. Importantly, the cues that mediate these opposing effects are not well understood. We propose here to generate tools to understand whether spleen glia play an unrecognized role in regulating these context-dependent effects of sympathetic outflow on adaptive immunity. Sympathetic terminals carrying adrenergic neurotransmitters enter the spleen around the arterial blood supply and innervate the white pulp, where antigen-specific T and B lymphocyte responses are continually developing. So glia accompanying the sympathetic nerves are optimally positioned to influence stress effects on antigen-dependent adaptive immune responses. The barrier to testing this is, however, that spleen glia have not previously been described. We are therefore requesting R21 funding to describe their anatomy and translatome (translating mRNAs), and to determine if they change their expression of immune genes during the extreme physiological stress of a large stroke. At the conclusion of these experiments, we will have generated tools to study not only spleen glia, but also other peripheral glia, and also have established whether spleen glia are important participants in sympathetically-mediated effects on immune responses. These studies are appropriate for R21 funding as they are high-risk initial studies in a new scientific area, the study of the functions of spleen glia.