title: Toll-like receptor ligands modulate dendritic cells to augment cytomegalovirus- and HIV-1-specific T cell responses.
abstract: Optimal Ag targeting and activation of APCs, especially dendritic cells (DCs), are important in vaccine development. In this study, we report the effects of different Toll-like receptor (TLR)-binding compounds to enhance immune responses induced by human APCs, including CD123(+) plasmacytoid DCs (PDCs), CD11c(+) myeloid DCs (MDCs), monocytes, and B cells. PDCs, which express TLR7 and TLR9, responded to imidazoquinolines (imiquimod and R-848) and to CpG oligodeoxynucleotides stimulation, resulting in enhancement in expression of costimulatory molecules and induction of IFN-alpha and IL-12p70. In contrast, MDCs, which express TLR3, TLR4, and TLR7, responded to poly(I:C), LPS, and imidazoquinolines with phenotypic maturation and high production of IL-12 p70 without producing detectable IFN-alpha. Optimally TLR ligand-stimulated PDCs or MDCs exposed to CMV or HIV-1 Ags enhanced autologous CMV- and HIV-1-specific memory T cell responses as measured by effector cytokine production compared with TLR ligand-activated monocytes and B cells or unstimulated PDCs and MDCs. Together, these data show that targeting specific DC subsets using TLR ligands can enhance their ability to activate virus-specific T cells, providing information for the rational design of TLR ligands as adjuvants for vaccines or immune modulating therapy.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-3022, USA. klore@mail.nih.gov
authors.forename: Karin
authors.initials: K
authors.lastname: Loré
authors.forename: Michael R
authors.initials: MR
authors.lastname: Betts
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Janaki
authors.initials: J
authors.lastname: Kuruppu
authors.forename: Soorena
authors.initials: S
authors.lastname: Khojasteh
authors.forename: Stephen
authors.initials: S
authors.lastname: Perfetto
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
authors.forename: Richard A
authors.initials: RA
authors.lastname: Koup
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism* / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000145:classification / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D003587:Cytomegalovirus / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D016898:Interferon-alpha / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D008024:Ligands; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000378:metabolism / Q000494:pharmacology; D011070:Poly I-C / Q000378:metabolism / Q000494:pharmacology; D021122:Protein Subunits / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000378:metabolism* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D018984:Epitopes, T-Lymphocyte; D007093:Imidazoles; D016898:Interferon-alpha; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D021122:Protein Subunits; D011956:Receptors, Cell Surface; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D018664:Interleukin-12; D011070:Poly I-C; C402365:resiquimod