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.

Comparative Systems Analyses Reveal Molecular Signatures of Clinically tested Vaccine Adjuvants

“…This is in accord with the observation that IC31 was the only adjuvant among the three without highly upregulated DEGs belonging to GO terms for innate inflammatory responses. The observed limited pro-inflammatory transcript expression is in line with a previous report that IC31 mainly targets monocyte-derived DCs by increasing the level of IFN-β and limiting the production of the pro-inflammatory cytokines TNF-α and IL-631.…”

Developing a preventive immunization approach against insect bite hypersensitivity using recombinant allergens: A pilot study

“…It stimulates the immune system via the TLR9/MyD88-dependent pathway. IC31 ® induces potent Th1 immune response in mice (Schellack et al, 2006) and it has been shown in vitro that IC31 ® modulates the cytokine profile of human dendritic cells which is important for protection against intracellular pathogens (Lingnau et al, 2007;Szabo et al, 2013). To our knowledge, this adjuvant has not been used in horses before.…”

Monocyte-derived dendritic cells from cirrhotic patients retain similar capacity for maturation/activation and antigen presentation as those from healthy subjects

“…By contrast, using cells from pre-tumor cirrhotic patients, we were able to expand potentially tumor-reactive multifunctional T-cells in a significant minority of subjects using 15mer peptide antigens. Further optimization of the approach with techniques such as codon-optimized DNA [44], co-transfection with cytokine -encoding DNA [45–47], or co-transfection with PAMPs [48–50] could increase the frequency of tumor-reactive T-cells generatable with cell-based vaccinations. We postulate that translation of an optimized MoDC approach using HCC-related antigens in pre-tumor cirrhotic patients has the potential to prevent or delay progression to hepatocellular carcinoma in this high risk population.…”