Sequential role of plasmacytoid dendritic cells and regulatory T cells in oral tolerance.
OBJECTIVE
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 CD3epsilon-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.
Université de Lyon, Lyon, IFR128, France. bertrand.dubois@inserm.fr
Bertrand
B
Dubois
Grégoire
G
Joubert
Mercedes
M
Gomez de Agüero
Marie
M
Gouanvic
Anne
A
Goubier
Dominique
D
Kaiserlian
D000284:Administration, Oral; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D003877:Dermatitis, Contact / Q000276:immunology; D004139:Dinitrofluorobenzene / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D007108:Immune Tolerance; D007114:Immunization; D016753:Interleukin-10 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008099:Liver / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D016131:Lymphocyte Subsets; D008643:Mesentery; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D006241:Haptens; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10; D004139:Dinitrofluorobenzene