期刊
GASTROENTEROLOGY
卷 137, 期 3, 页码 1019-1028出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2009.03.055
关键词
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资金
- Inserm
- INSERM poste d'accueil.
- Fondation pour la Recherche Medicale and Academie de Medecine
BACKGROUND & AIMS: Orally induced tolerance to environmental allergens prevents deleterious, systemic, delayed-type hypersensitivity responses via immune suppression mechanisms believed to include either anergy/deletion of specific effector T cells or active suppression by CD4(+)CD25(+) regulatory T cells (Tregs). The aim of this study was to investigate whether and how antigen (Ag) penetration through the gut orchestrates these 2 distinct mechanisms. METHODS: Using a model of allergic contact dermatitis (ACD) mediated by hapten-specific cytolytic CD8(+) T cells and a T-cell transfer model of contact hypersensitivity in CD3 epsilon-deficient mice, we studied the Outcome of Ag gavage on CD8(+) effectors and Tregs. RESULTS: Full protection from ACD by gavage with the relevant allergen required 2 coordinated events taking place first in gut-associated lymphoid tissues and then systemically. Allergen gavage induced deletion by plasmacytoid dendritic cells of a large fraction of Ag-specific CD8(+) T cells in liver and mesenteric lymph nodes and also triggered the suppressive function of Treg of secondary lymphoid organs. Residual Ag-specific CD8(+) T cells conditioned during this mucosal step are fully susceptible to suppression by activated Treg, which completely prevented their differentiation into ACD effectors, upon re-exposure to the allergen via the skin. CONCLUSIONS: Thus, oral tolerance initiated in gut-associated lymphoid tissues by the plasmacytoid dendritic cells-mediated deletion of Ag-specific T cells is completed systemically by CD4(+)CD25(+) T cells. Biotherapies able to increase the susceptibility of effector T cells to the suppressive function of Treg may be valuable for the treatment of autoimmune and inflammatory diseases.
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