Nociceptor-derived CGRP enhances dermal type I conventional dendritic cell function to drive autoreactive CD8+ T cell responses in vitiligo

Abstract

Vitiligo is an autoimmune disease characterized by depigmented patches of skin. Autoreactive CD8⁺ T cells kill melanocytes in vitiligo, but the immunopathogenesis remains elusive and ideal drug targets are lacking. Through single-cell and spatial transcriptomic analysis of vitiligo lesional skin, we found that conventional type 1 dendritic cells (cDC1s) primed CD8⁺ T cells and highly expressed the neuropeptide calcitonin gene-related peptide (CGRP) receptor. Deletion of Na_v1.8⁺ nociceptors, cDC1-specific ablation of the CGRP receptor, or treatment with a CGRP receptor antagonist (rimegepant) abrogated CD8⁺ T cell autoreactivity and prevented skin depigmentation in a mouse model of vitiligo. Conversely, CGRP administration restored vitiligo development in nociceptor-ablated mice. In a pilot study, topical application of rimegepant ointment alleviated skin depigmentation in individuals with vitiligo. Taken together, our results reveal that nociceptor-derived CGRP promotes cDC1-CD8⁺ T cell interactions and highlight CGRP receptor antagonism as a potential therapeutic strategy for treating vitiligo.