title: Lipopeptide epitopes extended by an Nepsilon-palmitoyl-lysine moiety increase uptake and maturation of dendritic cells through a Toll-like receptor-2 pathway and trigger a Th1-dependent protective immunity.
abstract: Lipopeptides, a form of peptide immunogens, are currently under intense investigation as human vaccines for many infectious pathogens and cancers. However, the cellular and molecular mechanisms of lipopeptide immunogenicity are only partially understood. We have investigated the influence of the lipid content on the immunogenicity of lipopeptides using the herpes simplex virus type 1 (HSV-1) gD(1-23) peptide as a model antigen. Totally synthetic lipopeptides were constructed by covalent attachment to the peptide backbone of either Nepsilon-palmitoyl-lysine (palmitoyl-lipidated peptide, palmitoyl-LP) or cholesterol-lysine (cholesterol-lipidated peptide, cholesterol-LP). Immunization of mice with the palmitoyl-LP, but not with its cholesterol-LP analog, induced a strong T cell-dependent protective immunity against lethal HSV-1 infection. Analysis of cytokine profiles and IgG2a/IgG1 ratios revealed that a dominant Th1-type immune response was stimulated by the palmitoyl-LP, as opposed to a Th2 response generated by its cholesterol-LP analog. The palmitoyl-LP was efficiently taken up in vitro by immature dendritic cells (DC) in a time- and dose-dependent manner, and induced phenotypic maturation and production of pro-inflammatory cytokines by DC. Finally, DC stimulated with the palmitoyl-LP induced antigen-specific T cell responses through the Toll-like receptor-2 pathway. These findings have important implications for the development of effective lipopeptide immunization strategies against infectious pathogens.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Department of Ophthalmology, University of California Irvine, College of Medicine, Irvine, CA 92868, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhu
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Ramos
authors.forename: Helene
authors.initials: H
authors.lastname: Gras-Masse
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kaplan
authors.forename: Lbachir
authors.initials: L
authors.lastname: BenMohamed
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002784:Cholesterol / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D000939:Epitopes / Q000276:immunology; D005260:Female; D006561:Herpes Simplex / Q000276:immunology* / Q000517:prevention & control; D022301:Herpes Simplex Virus Vaccines / Q000276:immunology* / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D008074:Lipoproteins / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D019308:Palmitic Acid / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014611:Vaccination; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: D000939:Epitopes; D022301:Herpes Simplex Virus Vaccines; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051195:Toll-Like Receptor 2; D051193:Toll-Like Receptors; D014759:Viral Envelope Proteins; D019308:Palmitic Acid; D002784:Cholesterol