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

Warakorn Kulalert, Alexandria C. Wells, Verena M. Link, Ai Ing Lim, Nicolas Bouladoux, Motoyoshi Nagai, Oliver J. Harrison, Olena Kamenyeva, Juraj Kabat, Michel Enamorado, Isaac M. Chiu, Yasmine Belkaid

Research output: Contribution to journalArticlepeer-review


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 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 in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. The 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.

Original languageEnglish (US)
Article numbere2322574121
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number11
StatePublished - Mar 12 2024
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


  • CGRP
  • T cells
  • microbiota
  • neuroimmune crosstalk


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