Defining cell type-specific immune responses in a mouse model of allergic contact dermatitis by single-cell transcriptomics

Author:

Liu Youxi1ORCID,Yin Meimei1ORCID,Mao Xiaoting2,Wu Shuai3ORCID,Wei Shuangping24,Heng Shujun1,Yang Yichun1,Huang Jinwen5,Guo Zhuolin6,Li Chuan2,Ji Chao5,Hu Liu2,Liu Wenjie1ORCID,Zhang Ling-juan1ORCID

Affiliation:

1. State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University

2. Zhejiang Yangshengtang Institute of Natural Medication Co Ltd

3. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University

4. Yang Sheng Tang (Anji) Cosmetics Co Ltd

5. Department of Dermatology, The First Affiliated Hospital of Fujian Medical University

6. Department of Dermatology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine

Abstract

Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+ or CD8+ lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+ lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8+ T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+ CD8+ T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Xiamen University Double First Class Construction Project

Publisher

eLife Sciences Publications, Ltd

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