CCR10 regulates balanced maintenance and function of resident regulatory and effector T cells to promote immune homeostasis in the skin

• Published in: Journal of allergy and clinical immunology 2014-09, Vol.134 (3), p.634-644.e10
• Main Authors: Xia, Mingcan, MD, PhD, Hu, Shaomin, MD, PhD, Fu, Yaoyao, MS, Jin, Wensen, MD, PhD, Yi, Qiyi, PhD, Matsui, Yurika, BS, Yang, Jie, BS, McDowell, Mary Ann, PhD, Sarkar, Surojit, PhD, Kalia, Vandana, PhD, Xiong, Na, PhD
• Format: Article
• Language: English
• Subjects: allergy; Allergy and Immunology; Animals; Assaults; Autoimmunity - genetics; Biological and medical sciences; Cells, Cultured; Chemokine CCL27 - metabolism; Chemokine receptor CCR10; Chemokines; dermatitis; Dermatitis, Atopic - immunology; Dermatology; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Homeostasis; Human subjects; Humans; immune homeostasis; Immune system; Immunity, Innate - genetics; Immunologic Memory; Immunopathology; inflammation; Inflammation - immunology; Laboratories; Leishmania species; Lymphocytes; maintenance; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Migration; Organ Specificity; Psoriasis; Psoriasis - immunology; Receptors, CCR10 - genetics; Receptors, CCR10 - metabolism; regulatory T cells; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin - immunology; skin infection; Skin involvement in other diseases. Miscellaneous. General aspects; skin-resident T cells; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - immunology; Up-Regulation; Wound healing
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2014.03.010

Background CCR10 and CCL27 make up the most skin-specific chemokine receptor/ligand pair implicated in skin allergy and inflammatory diseases, including atopic dermatitis and psoriasis. This pair is thought to regulate the migration, maintenance, or both of skin T cells and is suggested to be therapeutic targets for treatment of skin diseases. However, the functional importance of CCR10/CCL27 in vivo remains elusive. Objective We sought to determine the expression and function of CCR10 in different subsets of skin T cells under both homeostatic and inflammatory conditions to gain a mechanistic insight into the potential roles of CCR10 during skin inflammation. Methods Using heterozygous and homozygous CCR10 knockout/enhanced green fluorescent protein knockin mice, we assessed the expression of CCR10 on regulatory and effector T cells of healthy and inflamed skin induced by chemicals, pathogens, and autoreactive T cells. In addition, we assessed the effect of CCR10 knockout on the maintenance and functions of different T cells and inflammatory status in the skin during different phases of the immune response. Results CCR10 expression is preferentially induced on memory-like skin-resident T cells and their progenitors for their maintenance in homeostatic skin but not expressed on most skin-infiltrating effector T cells during inflammation. In CCR10 knockout mice the imbalanced presence and dysregulated function of resident regulatory and effector T cells result in over-reactive and prolonged innate and memory responses in the skin, leading to increased clearance of Leishmania species infection in the skin. Conclusion CCR10 is a critical regulator of skin immune homeostasis.