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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / pharmacology
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cells, Cultured
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Chemokines / immunology
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Drug Combinations
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Endosomes / drug effects
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Endosomes / immunology*
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Humans
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I-kappa B Proteins / biosynthesis
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I-kappa B Proteins / immunology
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Interferon Regulatory Factor-3 / immunology
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Interferon Type I / biosynthesis*
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Interferon Type I / immunology
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Interferon-beta / immunology
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Interleukin-6 / immunology
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Leukocytes, Mononuclear / drug effects*
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Leukocytes, Mononuclear / immunology
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Ligation
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NF-KappaB Inhibitor alpha
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NF-kappa B / immunology
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Oligodeoxyribonucleotides / immunology
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Oligodeoxyribonucleotides / pharmacology*
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Oligopeptides / immunology
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Oligopeptides / pharmacology*
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Phosphorylation
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Toll-Like Receptors / immunology*
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Tumor Necrosis Factor-alpha / immunology
Substances
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Adjuvants, Immunologic
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Chemokines
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Drug Combinations
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I-kappa B Proteins
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IC31 adjuvant
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IRF3 protein, human
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Interferon Regulatory Factor-3
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Interferon Type I
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Interleukin-6
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NF-kappa B
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NFKBIA protein, human
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Oligodeoxyribonucleotides
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Oligopeptides
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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NF-KappaB Inhibitor alpha
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Interferon-beta
Grants and funding
The experimental work was supported by the National Scientific Research grant OTKA NK-10-15-38 and TÁMOP 4.2.1./B-09/1/KONV-2010-0007 both to ER. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.