Anatomically distinct fibroblast subsets determine skin autoimmune patterns

Zijian Xu, Daoming Chen, Yucheng Hu, Kaiju Jiang, Huanwei Huang, Yingxue Du, Wenbo Wu, Jiawen Wang, Jianhua Sui, Wenhui Wang, Long Zhang, Shuli Li, Chunying Li, Yong Yang, Jianmin Chang () and Ting Chen ()
Additional contact information
Zijian Xu: National Institute of Biological Sciences
Daoming Chen: National Institute of Biological Sciences
Yucheng Hu: Capital Normal University
Kaiju Jiang: National Institute of Biological Sciences
Huanwei Huang: National Institute of Biological Sciences
Yingxue Du: National Institute of Biological Sciences
Wenbo Wu: National Institute of Biological Sciences
Jiawen Wang: National Institute of Biological Sciences
Jianhua Sui: National Institute of Biological Sciences
Wenhui Wang: Peking University Third Hospital
Long Zhang: Peking University Third Hospital
Shuli Li: Xijing Hospital
Chunying Li: Xijing Hospital
Yong Yang: Chinese Academy of Medical Sciences and Peking Union Medical College
Jianmin Chang: Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences
Ting Chen: National Institute of Biological Sciences

Nature, 2022, vol. 601, issue 7891, 118-124

Abstract: Abstract The skin serves as a physical barrier and an immunological interface that protects the body from the external environment1–3. Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions of the body4–6. Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8+ T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8+ cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases.

Date: 2022
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DOI: 10.1038/s41586-021-04221-8

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