Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells.
Oral tolerance induction is a key feature of intestinal immunity, generating systemic nonresponsiveness to ingested antigens. In this study, we report that orally applied soluble antigens are exclusively recognized in the intestinal immune system, particularly in the mesenteric lymph nodes. Consequently, the initiation of oral tolerance is impeded by mesenteric lymphadenectomy. Small bowel transplantation reveals that mesenteric lymph nodes require afferent lymph to accomplish the recognition of orally applied antigens. Finally, oral tolerance cannot be induced in CCR7-deficient mice that display impaired migration of dendritic cells from the intestine to the mesenteric lymph nodes, suggesting that immunologically relevant antigen is transported in a cell-bound fashion. These results demonstrate that antigen transport via afferent lymphatics into the draining mesenteric lymph nodes is obligatory for oral tolerance induction, inspiring new therapeutic strategies to exploit oral tolerance induction for the prevention and treatment of autoimmune diseases.
Institute of Immunology, Department of Visceral and Transplantation Surgery, Hannover Medical School, 30625 Hannover, Germany.
Tim
T
Worbs
Ulrike
U
Bode
Sheng
S
Yan
Matthias W
MW
Hoffmann
Gabriele
G
Hintzen
Günter
G
Bernhardt
Reinhold
R
Förster
Oliver
O
Pabst
D000284:Administration, Oral; D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D018928:Immunity, Mucosal; D007421:Intestine, Small / Q000276:immunology / Q000637:transplantation; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000172:deficiency / Q000276:immunology*
D000941:Antigens; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D019707:Receptors, Chemokine