The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota.

Unlabelled: The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide Calcitonin Gene-Related Peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers . Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8 T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology.

Significance Statement: Multisystem coordination at barrier surfaces is critical for optimal tissue functions and integrity, in response to microbial and environmental cues. In this study, we identified a novel neuroimmune crosstalk mechanism between the sensory nervous system and the adaptive immune response to the microbiota, mediated by the neuropeptide CGRP and its receptor RAMP1 on skin microbiota-induced T lymphocytes. The neuroimmune CGPR-RAMP1 axis constrains adaptive immunity to the microbiota and overall limits the activation status of the skin epithelium, impacting tissue responses to wounding. Our study opens the door to a new avenue to modulate adaptive immunity to the microbiota utilizing neuromodulators, allowing for a more integrative and tailored approach to harnessing microbiota-induced T cells to promote barrier tissue protection and repair.