title: Type I IFN-mediated synergistic activation of mouse and human DC subsets by TLR agonists.
abstract: Novel approaches of dendritic cell (DC) based cancer immunotherapy aim at harnessing the unique attributes of different DC subsets. Classical monocyte-derived DC vaccines are currently being replaced by either applying primary DCs or specifically targeting antigens and adjuvants to these subsets in vivo. Appropriate DC activation in both strategies is essential for optimal effect. For this purpose TLR agonists are favorable adjuvant choices, with TLR7 triggering being essential for inducing strong Th1 responses. However, mouse CD8α(+) DCs, considered to be the major cross-presenting subset, lack TLR7 expression. Interestingly, this DC subset can respond to TLR7 ligand upon concurrent TLR3 triggering. Nevertheless, the mechanism underlying this synergy remains obscure. We now show that TLR3 ligation results in the production of IFN-α, which rapidly induces the expression of TLR7, resulting in synergistic activation. Moreover, we demonstrate that this mechanism conversely holds for plasmacytoid DCs that respond to TLR3 ligation when TLR7 pathway is mobilized. We further demonstrate that this mechanism of sharpening DC senses is also conserved in human BDCA1(+) DCs and plasmacytoid DCs. These findings have important implications for future clinical trials as it suggests that combinations of TLR ligands should be applied irrespective of initial TLR expression profiles on natural DC subsets for optimal stimulation.
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Kreutz
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Ghaith
authors.initials: G
authors.lastname: Bakdash
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Dolen
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Oncology and Pathology, Karolinska University Hospital Solna, Karolinska Institute, Stockholm, Sweden.
authors.forename: Annette E
authors.initials: AE
authors.lastname: Sköld
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Maaike A
authors.initials: MA
authors.lastname: van Hout-Kuijer
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: I Jolanda M
authors.initials: IJ
authors.lastname: de Vries
authors.affiliation: Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Figdor
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000276:immunology; D051379:Mice; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000276:immunology
chemical_list: D007370:Interferon Type I; D008562:Membrane Glycoproteins; C495344:TLR3 protein, human; C519703:TLR3 protein, mouse; C495348:TLR7 protein, human; C477038:Tlr7 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7
keywords: Adjuvants ⋅ Dendritic cells ⋅ Synergy ⋅ Toll-like receptors ⋅ Type I IFN