Sequential Role of Plasmacytoid Dendritic Cells and Regulatory T Cells in Oral Tolerance

Background & AimsOrally 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.MethodsUsing 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 CD3ε-deficient mice, we studied the outcome of Ag gavage on CD8+ effectors and Tregs.ResultsFull 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.ConclusionsThus, 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.