title: Dendritic cell function can be modulated through cooperative actions of TLR ligands and invariant NKT cells.
abstract: The quality of signals received by dendritic cells (DC) in response to pathogens influences the nature of the adaptive response. We show that pathogen-derived signals to DC mediated via TLRs can be modulated by activated invariant NKT (iNKT) cells. DC maturation induced in vivo with any one of a variety of TLR ligands was greatly improved through simultaneous administration of the iNKT cell ligand alpha-galactosylceramide. DC isolated from animals treated simultaneously with TLR and iNKT cell ligands were potent stimulators of naive T cells in vitro compared with DC from animals treated with the ligands individually. Injection of protein Ags with both stimuli resulted in significantly improved T cell and Ab responses to coadministered protein Ags over TLR stimulation alone. Ag-specific CD8(+) T cell responses induced in the presence of the TLR4 ligand monophosphoryl lipid A and alpha-galactosylceramide showed faster proliferation kinetics, and increased effector function, than those induced with either ligand alone. Human DC exposed to TLR ligands and activated iNKT cells in vitro had enhanced expression of maturation markers, suggesting that a cooperative action of TLR ligands and iNKT cells on DC function is a generalizable phenomenon across species. These studies highlight the potential for manipulating the interactions between TLR ligands and iNKT cell activation in the design of effective vaccine adjuvants.
authors.affiliation: Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Hermans
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Silk
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.forename: S Hajar
authors.initials: SH
authors.lastname: Masri
authors.forename: Dawn
authors.initials: D
authors.lastname: Shepherd
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Farrand
authors.forename: Mariolina
authors.initials: M
authors.lastname: Salio
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005699:Galactosylceramides / Q000276:immunology* / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008050:Lipid A / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D015415:Biomarkers; D005699:Galactosylceramides; D008024:Ligands; D008050:Lipid A; D051193:Toll-Like Receptors; C493154:alpha-galactosylceramide; C048436:monophosphoryl lipid A