Systematic mapping of neural signals in the periphery reveals a rich and specific alphabet for immune cell communication

Summary Accumulating evidence indicate a strong link between neural signals and the immune system. Given neural signals constitute a large family that may be leveraged for communication, we systematically explored the neuro-immune regulation network in the periphery and uncovered a broad yet lineage selective expression of neuro-receptors on immune cells. We constructed a rich social immune network map showing the neural molecular pathways supporting the regulation of the immune system at steady state. Our results emphasize neuro-receptors role in the commitment and differentiation of B and T cells along their developmental process. We identified the immune cells’ functionality in the specific tissue is extensively shaped by the communication with the microenvironment and nervous systems via a rich alphabet of neural mediators. Collectively, our findings suggest neural genes are an integral part of the immune regulatory system and provide clear testable new avenues of experimental follow up for neuroimmunologists and immunologists alike. Abstract Figure Highlights 160 neural genes potentially active in immune cells in the periphery with high specificity to lineage Neuro-receptors co-expressed in immune lineages are enriched for biological functions Changes in neuro-receptors expression influence the HCS differentiation and commitment Immune-microenvironment neural signaling architecture reflects tissue biological role