title: Splenic marginal zone dendritic cells mediate the cholera toxin adjuvant effect: dependence on the ADP-ribosyltransferase activity of the holotoxin.
abstract: The in vivo mechanisms of action of most vaccine adjuvants are poorly understood. In this study, we present data in mice that reveal a series of critical interactions between the cholera toxin (CT) adjuvant and the dendritic cells (DC) of the splenic marginal zone (MZ) that lead to effective priming of an immune response. For the first time, we have followed adjuvant targeting of MZ DC in vivo. We used CT-conjugated OVA and found that the Ag selectively accumulated in MZ DC following i.v. injections. The uptake of Ag into DC was GM1 ganglioside receptor dependent and mediated by the B subunit of CT (CTB). The targeted MZ DC were quite unique in their phenotype: CD11c(+), CD8alpha(-), CD11b(-), B220(-), and expressing intermediate or low levels of MHC class II and DEC205. Whereas CTB only delivered the Ag to MZ DC, the ADP-ribosyltransferase activity of CT was required for the maturation and migration of DC to the T cell zone, where these cells distinctly up-regulated CD86, but not CD80. This interaction appeared to instruct Ag-specific CD4(+) T cells to move into the B cell follicle and strongly support germinal center formations. These events may explain why CT-conjugated Ag is substantially more immunogenic than Ag admixed with soluble CT and why CTB-conjugated Ag can tolerize immune responses when given orally or at other mucosal sites.
authors.affiliation: Department of Clinical Immunology, University of Göteborg, Göteborg, Sweden.
authors.forename: Dubravka
authors.initials: D
authors.lastname: Grdic
authors.forename: Lena
authors.initials: L
authors.lastname: Ekman
authors.forename: Karin
authors.initials: K
authors.lastname: Schön
authors.forename: Kristina
authors.initials: K
authors.lastname: Lindgren
authors.forename: Johan
authors.initials: J
authors.lastname: Mattsson
authors.forename: Karl-Eric
authors.initials: KE
authors.lastname: Magnusson
authors.forename: Paola
authors.initials: P
authors.lastname: Ricciardi-Castagnoli
authors.forename: Nils
authors.initials: N
authors.lastname: Lycke
mesh_terms: D036002:ADP Ribose Transferases / Q000276:immunology / Q000502:physiology*; D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000276:immunology / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011956:Receptors, Cell Surface / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D011956:Receptors, Cell Surface; C034993:ganglioside receptor; D010047:Ovalbumin; D002772:Cholera Toxin; D036002:ADP Ribose Transferases