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

Xiuli Yang; Wenxiang Ding; Fangzhou Lou; Hao Xu; Anqi Sheng; Yang Sun; Xiaojie Cai; Miaoni Zhou; Fuquan Lin; Rong Jin; Xichen Zheng; Zhikai Wang; Siyu Deng; Zhenyao Xu; Taiyu Zhang; Jinke Cheng; Xingdong Zheng; Aie Xu; Honglin Wang

doi:10.1016/j.immuni.2025.05.018

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

Immunity. 2025 Aug 12;58(8):2086-2103.e9. doi: 10.1016/j.immuni.2025.05.018. Epub 2025 Jun 16.

Authors

Xiuli Yang¹, Wenxiang Ding², Fangzhou Lou², Hao Xu³, Anqi Sheng³, Yang Sun², Xiaojie Cai², Miaoni Zhou³, Fuquan Lin³, Rong Jin³, Xichen Zheng², Zhikai Wang², Siyu Deng², Zhenyao Xu², Taiyu Zhang², Jinke Cheng⁴, Xingdong Zheng⁵, Aie Xu⁶, Honglin Wang⁷

Affiliations

¹ Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
³ Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, China; Zhejiang University School of Medicine, Hangzhou, China.
⁴ Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁵ Total Quality Management Institute, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China. Electronic address: zhengxingdong2020@163.com.
⁶ Department of Dermatology, Hangzhou Third People's Hospital, Hangzhou, China; Zhejiang University School of Medicine, Hangzhou, China. Electronic address: xuaiehz@msn.com.
⁷ Precision Research Center for Refractory Diseases, Shanghai Jiao Tong University Pioneer Research Institute for Molecular and Cell Therapies, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China; State Key Laboratory of Innovative Immunotherapy, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: honglin.wang@sjtu.edu.cn.

PMID: 40527324
DOI: 10.1016/j.immuni.2025.05.018

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.

Keywords: CGRP; autoreactive CD8(+) T cells; cDC1s; nociceptors; vitiligo.

MeSH terms

Animals
Autoimmunity
CD8-Positive T-Lymphocytes* / immunology
Calcitonin Gene-Related Peptide Receptor Antagonists / pharmacology
Calcitonin Gene-Related Peptide* / immunology
Calcitonin Gene-Related Peptide* / metabolism
Dendritic Cells* / immunology
Disease Models, Animal
Female
Humans
Male
Melanocytes / immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Nociceptors* / immunology
Nociceptors* / metabolism
Receptors, Calcitonin Gene-Related Peptide / genetics
Receptors, Calcitonin Gene-Related Peptide / metabolism
Skin / immunology
Skin / pathology
Vitiligo* / drug therapy
Vitiligo* / immunology
Vitiligo* / metabolism
Vitiligo* / pathology

Substances

Calcitonin Gene-Related Peptide
Receptors, Calcitonin Gene-Related Peptide
Calcitonin Gene-Related Peptide Receptor Antagonists