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 Vol. 134; no. 3; pp. 634 - 644.e10
• Main Authors: Xia, Mingcan, Hu, Shaomin, Fu, Yaoyao, Jin, Wensen, Yi, Qiyi, Matsui, Yurika, Yang, Jie, McDowell, Mary Ann, Sarkar, Surojit, Kalia, Vandana, Xiong, Na
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.09.2014; Elsevier; Elsevier Limited
• 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; TCR; TPA; Leishmania species; immune homeostasis; BM; FACS; EGFP; Chemokine receptor CCR10; skin-resident T cells; CHS; FITC; dermatitis; inflammation; WT; DNFB; Treg; allergy; regulatory T cells; PE; skin infection; Teff; migration; OVA; Foxp3; maintenance; T-cell receptor; Forkhead box protein 3; Bone marrow; Regulatory T; Fluorescein 5-isothiocyanate; Enhanced green fluorescent protein; Ovalbumin; Effector T; Wild-type; Fluorescence-activated cell sorting; 12-O-tetradecanoyl-phorbol-13-acetate; Phycoerythrin; 2,4-Dinitro-1-fluorobenzene; Contact hypersensitivity; Allergy; Skin disease; Homeostasis; Chemokine receptor; Dermatitis; Regulation(control); Immunology; T-Lymphocyte; Resident; Species; Regulatory cell; Kinetoplastida; Human; Protozoa; Immunopathology; CCR10 chemokine receptor; Inflammation; Effector; Infection; Leishmania; Resident (student); Skin; Cell migration
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2014.03.010

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. 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. 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. 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. CCR10 is a critical regulator of skin immune homeostasis.