title: The TLR7/8 ligand resiquimod targets monocyte-derived dendritic cell differentiation via TLR8 and augments functional dendritic cell generation.
abstract: Imidazoquinolone compounds, such as resiquimod are Toll-like receptor (TLR) 7/8 ligands representing novel immune response modifiers undergoing clinical testing. Resiquimod has been reported to modulate conventional human monocyte-derived DC (moDC) differentiation, but the role of TLR7 and TLR8 is unclear. We directly dissected the TLR7- and TLR8-dependency by employing selective TLR7 ligands and resiquimod-coculture experiments with inhibitory oligonucleotides (iODN) suppressing TLR7, TLR7+8 or TLR7+8+9. Selective TLR7 ligands did not affect conventional moDC differentiation as analyzed by CD14/CD1a expression. iODN experiments confirmed that resiquimod's effects during DC differentiation were antagonized only with TLR8 iODNs. Direct comparison of resiquimod DC with TLR7- and control-DC revealed significantly higher T-cell costimulatory molecule and MHC class II expression. Resiquimod DC promoted significantly stronger allogeneic T-cell proliferation and stronger naïve CD4(+) T-cell proliferation. These results indicate the relevance of TLR8 for human monocyte-derived DC differentiation and maturation and may be relevant for clinical trials employing resiquimod.
authors: Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, Giessen, Germany. Holger.Hackstein@immunologie.med.uni-giessen.de
authors: Holger
authors: H
authors: Hackstein
authors: Angela
authors: A
authors: Knoche
authors: Angelika
authors: A
authors: Nockher
authors: Jochen
authors: J
authors: Poeling
authors: Thomas
authors: T
authors: Kubin
authors: Marion
authors: M
authors: Jurk
authors: Jörg
authors: J
authors: Vollmer
authors: Gregor
authors: G
authors: Bein
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D006151:Guanosine / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D006681:HLA-D Antigens / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D053650:Interleukin-3 Receptor alpha Subunit / Q000378:metabolism; D008024:Ligands; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors / Q000235:genetics; D014162:Transfection
chemical_list: D000634:Aminoquinolines; D006681:HLA-D Antigens; C115022:IL3RA protein, human; D007093:Imidazoles; D053650:Interleukin-3 Receptor alpha Subunit; D008024:Ligands; D020319:Oligodeoxyribonucleotides, Antisense; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9; C546771:gardiquimod; D006151:Guanosine; C068562:loxoribine; C402365:resiquimod