Crosstalk of regulatory T cells and tolerogenic dendritic cells prevents contact allergy in subjects with low zone tolerance

• Published in: Journal of allergy and clinical immunology Vol. 130; no. 3; pp. 781 - 797.e11
• Main Authors: Luckey, Ulrike, Schmidt, Talkea, Pfender, Nikolai, Romer, Maike, Lorenz, Nadine, Martin, Stefan F., Bopp, Tobias, Schmitt, Edgar, Nikolaev, Alexey, Yogev, Nir, Waisman, Ari, Jakob, Thilo, Steinbrink, Kerstin
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.09.2012; Elsevier; Elsevier Limited
• Subjects: Adoptive transfer; Allergens; allergic contact dermatitis; Allergies; Allergy and Immunology; Animal models; Animals; Autoimmune diseases; Biological and medical sciences; CD11c antigen; CD11c Antigen - analysis; CD25 antigen; CD4 antigen; CD8 antigen; Cell Communication; Cell interactions; Communications; contact allergen; Contact dermatitis; contact hypersensitivity; Cytokines; Data processing; Dendritic cells; Dendritic Cells - physiology; Dermatitis, Allergic Contact - immunology; Dermatitis, Allergic Contact - prevention & control; Education; Flow cytometry; Forkhead protein; Forkhead Transcription Factors - analysis; Foxp3 protein; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gap junctions; hapten; Hypersensitivity; IL-10; Immune Tolerance; Immunological tolerance; Immunopathology; Immunoregulation; Interleukin 10; Interleukin-10 - physiology; Interleukin-2 Receptor alpha Subunit - physiology; low zone tolerance; Lymph nodes; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Medical sciences; Mice; Mice, Transgenic; Occupational diseases; phenotype; Proteins; Receptors, CCR7 - analysis; regulatory T cells; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin; Software; Spleen; T-lymphocytes; T-Lymphocytes, Regulatory - physiology; Tolerance; Germany; CD62L; GITR; LN; LZT; CHS; DT; GFP; contact allergen; dendritic cells; CTLA-4; ICOS; WT; AOO; low zone tolerance; hapten; allergic contact dermatitis; DNFB; Treg; Tolerance; contact hypersensitivity; FOXP3; IL-10; regulatory T cells; TNCB; DC; 1-Fluoro-2,4-dinitrobenzene; Glucocorticoid-induced TNF receptor family-related gene; Forkhead box protein 3; Cytotoxic T lymphocyte–associated antigen 4; Regulatory T; Acetone/olive oil; Diphtheria toxin; CD62 ligand; Dendritic cell; Lymph node; 2,4,6-Trinitro-1-chlorobenzene; Inducible costimulator; Wild-type; Green fluorescent protein; Allergy; Skin disease; Prevention; Immunology; Antigen presenting cell; T-Lymphocyte; Regulatory cell; Human; Immunopathology; Cytokine; Hapten; Cell contact; Contact dermatitis; Immune tolerance; Interleukin 10; Allergen; Contact hypersensitivity
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2012.06.022

Allergic contact dermatitis is one of the most common occupational diseases. A main protective mechanism in those who do not develop allergic contact dermatitis is tolerance induction by repeated exposure to low doses of contact allergen, which is termed low zone tolerance (LZT). The mechanisms that determine the tolerance induction in subjects with LZT are still elusive. We performed analysis of the role of CD4+CD25+ forkhead box protein 3 (FOXP3)–positive regulatory T (Treg) cells and dendritic cells (DCs) in mice with LZT. Mechanisms of tolerance induction were analyzed in a murine model of LZT by using FOXP3 and IL-10 reporter mice, as well as mice that allow the selective depletion of Treg cells or DCs. Depletion of CD4+CD25+FOXP3+ Treg cells during tolerance induction completely abolishes the development of LZT, resulting in a pronounced contact hypersensitivity response. Adoptive transfer experiments, depletion studies, and use of cell type–specific deficient mice revealed that IL-10 production is critical for the suppressor function of Treg cells in mice with LZT and that tolerogenic CD8+CD11c+ DCs located in the skin-draining lymph nodes are essential for LZT. In the absence of Treg cells, DCs did not develop tolerogenic functions, indicating that activated IL-10+ Treg cells might imprint the tolerogenic DC phenotype. Cell communication analysis revealed that the education of tolerogenic DCs might involve a direct interaction with Treg cells mediated by gap junctions. Subsequently, induction of tolerogenic CD11c+ DCs leads to the generation of hapten-specific CD8+ Treg cells, which protect against contact hypersensitivity. Our data demonstrate critical interactions between CD4+CD25+FOXP3+ Treg cells and tolerogenic CD8+CD11c+ DCs during the induction of LZT.