title: Colonic tolerance develops in the iliac lymph nodes and can be established independent of CD103(+) dendritic cells.
abstract: Tolerance to harmless exogenous antigens is the default immune response in the gastrointestinal tract. Although extensive studies have demonstrated the importance of the mesenteric lymph nodes (MLNs) and intestinal CD103(+) dendritic cells (DCs) in driving small intestinal tolerance to protein antigen, the structural and immunological basis of colonic tolerance remain poorly understood. We show here that the caudal and iliac lymph nodes (ILNs) are inductive sites for distal colonic immune responses and that colonic T cell-mediated tolerance induction to protein antigen is initiated in these draining lymph nodes and not in MLNs. In agreement, colonic tolerance induction was not altered by mesenteric lymphadenectomy. Despite tolerance development, CD103(+)CD11b(+) DCs, which are the major migratory DC population in the MLNs, and the tolerance-related retinoic acid-generating enzyme RALDH2 were virtually absent from the ILNs. Administration of ovalbumin (OVA) to the distal colon did increase the number of CD11c(+)MHCII(hi) migratory CD103(-)CD11b(+) and CD103(+)CD11b(-) DCs in the ILNs. Strikingly, colonic tolerance was intact in Batf3-deficient mice specifically lacking CD103(+)CD11b(-) DCs, suggesting that CD103(-) DCs in the ILNs are sufficient to drive tolerance induction after protein antigen encounter in the distal colon. Altogether, we identify different inductive sites for small intestinal and colonic T-cell responses and reveal that distinct cellular mechanisms are operative to maintain tolerance at these sites.
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Veenbergen
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: van Berkel
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: M F
authors.initials: MF
authors.lastname: du Pré
authors.affiliation: Mucosal Immunobiology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Karrich
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: L M M
authors.initials: LM
authors.lastname: Costes
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Luk
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Simons-Oosterhuis
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: H C
authors.initials: HC
authors.lastname: Raatgeep
authors.affiliation: Institute of Molecular Medicine, RWTH Aachen, Aachen, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Cerovic
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Cupedo
authors.affiliation: Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Mowat
authors.affiliation: Mucosal Immunobiology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Kelsall
authors.affiliation: Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: J N
authors.initials: JN
authors.lastname: Samsom
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics; D039481:CD11b Antigen / Q000378:metabolism; D003106:Colon / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D007084:Iliac Vein / Q000033:anatomy & histology; D007108:Immune Tolerance; D039001:Integrin alpha Chains / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology*; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000033:anatomy & histology / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D050976:Basic-Leucine Zipper Transcription Factors; D039481:CD11b Antigen; D039001:Integrin alpha Chains; D012097:Repressor Proteins; C533289:SNFT protein, mouse; C091367:alpha E integrins; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse