title: Targeting the gut vascular endothelium induces gut effector CD8 T cell responses via cross-presentation by dendritic cells.
abstract: Systemic delivery of Ag usually induces poor mucosal immunity. To improve the CD8 T cell response at mucosal sites, we targeted the Ag to MAdCAM-1, a mucosal addressin cell adhesion molecule expressed mainly by high endothelial venules (HEV) in mesenteric lymph nodes (MLN) and Peyer's patches of gut-associated lymphoid tissue. When chemical conjugates of anti-MAdCAM-1 Ab and model Ag OVA were injected i.v., a greatly enhanced proliferative response of Ag-specific OT-I CD8 T cells was detected in MLN. This was preceded by prolonged accumulation, up to 2 wk, of the anti-MAdCAM OVA conjugate on HEV of Peyer's patches and MLN. In contrast, nontargeted OVA conjugate was very inefficient in inducing OT-I CD8 T cell proliferation in MLN and required at least 20-fold more Ag to induce a comparable response. In addition, MAdCAM targeting elicits an endogenous OVA-specific CD8 T cell response, evident by IFN-gamma production and target killing. Induced response offers protection against an OVA-expressing B cell lymphoma. We propose that the augmentation of gut CD8 T cell responses by MAdCAM targeting is due to both accumulation of Ag in the HEV and conversion of a soluble Ag to a cell-associated one, allowing cross-presentation by DCs.
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Bourges
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhan
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Brady
authors.forename: Hal
authors.initials: H
authors.lastname: Braley
authors.forename: Irina
authors.initials: I
authors.lastname: Caminschi
authors.forename: Sandro
authors.initials: S
authors.lastname: Prato
authors.forename: José A
authors.initials: JA
authors.lastname: Villadangos
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lew
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D045142:Cross-Priming / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007422:Intestines / Q000276:immunology*; D015448:Leukemia, B-Cell / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology
chemical_list: D000941:Antigens; D039521:CD11c Antigen; D015815:Cell Adhesion Molecules; D015395:Histocompatibility Antigens Class I; D010047:Ovalbumin