title: The two-component adjuvant IC31® boosts type i interferon production of human monocyte-derived dendritic cells via ligation of endosomal TLRs.
abstract: The aim of this study was to characterize and identify the mode of action of IC31®, a two-component vaccine adjuvant. We found that IC31® was accumulated in human peripheral blood monocytes, MHC class II positive cells and monocyte-derived DCs (moDCs) but not in plasmacytoid DCs (pDCs). In the presence of IC31® the differentiation of inflammatory CD1a(+) moDCs and the secretion of chemokines, TNF-α and IL-6 cytokines was inhibited but the production of IFNβ was increased. Sustained addition of IC31® to differentiating moDCs interfered with IκBα phosphorylation, while the level of phospho-IRF3 increased. We also showed that both IC31® and its KLK component exhibited a booster effect on type I IFN responses induced by the specific ligands of TLR3 or TLR7/8, whereas TLR9 ligand induces type I IFN production only in the presence of IC31® or ODN1. Furthermore, long term incubation of moDCs with IC31® caused significantly higher expression of IRF and IFN genes than a single 24 hr treatment. The adjuvant activity of IC31® on the IFN response was shown to be exerted through TLRs residing in the vesicular compartment of moDCs. Based on these results IC31® was identified as a moDC modulatory adjuvant that sets the balance of the NF-κB and IRF3 mediated signaling pathways to the production of IFNβ. Thus IC31® is emerging as a potent adjuvant to increase immune responses against intracellular pathogens and cancer in future vaccination strategies.
authors: Department of Immunology, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary.
authors: Attila
authors: A
authors: Szabo
authors: Peter
authors: P
authors: Gogolak
authors: Kitti
authors: K
authors: Pazmandi
authors: Katalin
authors: K
authors: Kis-Toth
authors: Karin
authors: K
authors: Riedl
authors: Benjamin
authors: B
authors: Wizel
authors: Karen
authors: K
authors: Lingnau
authors: Attila
authors: A
authors: Bacsi
authors: Bence
authors: B
authors: Rethi
authors: Eva
authors: E
authors: Rajnavolgyi
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D004338:Drug Combinations; D011992:Endosomes / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology; D008026:Ligation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D009842:Oligopeptides / Q000276:immunology / Q000494:pharmacology*; D010766:Phosphorylation; D051193:Toll-Like Receptors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D018925:Chemokines; D004338:Drug Combinations; D020672:I-kappa B Proteins; C544002:IC31 adjuvant; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D016899:Interferon-beta
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