title: Cholera toxin promotes the induction of regulatory T cells specific for bystander antigens by modulating dendritic cell activation.
abstract: It has previously been reported that cholera toxin (CT) is a potent mucosal adjuvant that enhances Th2 or mixed Th1/Th2 type responses to coadministered foreign Ag. Here we demonstrate that CT also promotes the generation of regulatory T (Tr) cells against bystander Ag. Parenteral immunization of mice with Ag in the presence of CT induced T cells that secreted high levels of IL-4 and IL-10 and lower levels of IL-5 and IFN-gamma. Ag-specific CD4(+) T cell lines and clones generated from these mice had cytokine profiles characteristic of Th2 or type 1 Tr cells, and these T cells suppressed IFN-gamma production by Th1 cells. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (DC) incubated with Ag and CT induced T cells that secreted IL-4 and IL-10 and low concentrations of IL-5. It has previously been shown that IL-10 promotes the differentiation or expansion of type 1 Tr cells. Here we found that CT synergized with low doses of LPS to induce IL-10 production by immature DC. CT also enhanced the expression of CD80, CD86, and OX40 (CD134) on DC and induced the secretion of the chemokine, macrophage inflammatory protein-2 (MIP-2), but inhibited LPS-driven induction of CD40 and ICAM-I expression and production of the inflammatory cytokines/chemokines IL-12, TNF-alpha, MIP-1alpha, MIP-1beta, and monocyte chemoattractant protein-1. Our findings suggest that CT induces maturation of DC, but, by inducing IL-10, inhibiting IL-12, and selectively affecting surface marker expression, suppresses the generation of Th1 cells and promotes the induction of T cells with regulatory activity.
authors.affiliation: Immune Regulation Research Group, Department of Biochemistry, Trinity College, Dublin 2, Ireland.
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
authors.forename: Edel
authors.initials: E
authors.lastname: McNeela
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Armstrong
authors.forename: Olive
authors.initials: O
authors.lastname: Leavy
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Higgins
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D024201:Bystander Effect / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D054426:Chemokine CXCL2; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002772:Cholera Toxin / Q000008:administration & dosage / Q000494:pharmacology*; D002999:Clone Cells; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006433:Hemocyanins / Q000008:administration & dosage / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016753:Interleukin-10; D007371:Interferon-gamma; D002772:Cholera Toxin; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin