The two-component adjuvant IC31® boosts type i interferon production of human monocyte-derived dendritic cells via ligation of endosomal TLRs.
The two-component adjuvant IC31® boosts type i interferon production of human monocyte-derived dendritic cells via ligation of endosomal TLRs.
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DOI：
10.1371/journal.pone.0055264
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rajnavolgyi E
中科院分区：
文献类型：
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作者：
Szabo A;Gogolak P;Pazmandi K;Kis-Toth K;Riedl K;Wizel B;Lingnau K;Bacsi A;Rethi B;Rajnavolgyi E
本研究的目的是表征和鉴定双组分疫苗佐剂IC31®的作用方式。我们发现，IC31在人外周血单核细胞、MHCⅱ类阳性细胞和单核细胞来源的dc （moDCs）中积累，但在浆细胞样dc （pDCs）中不积累。在IC31的存在下，炎性CD1a+ moDCs的分化和趋化因子、TNF-α和IL-6细胞因子的分泌被抑制，IFNβ的产生增加。在分化的moDCs中持续添加IC31®会干扰IκBα磷酸化，同时磷酸化irf3水平升高。我们还发现，IC31®及其KLK成分对TLR3或TLR7/8特异性配体诱导的I型IFN反应具有增强作用，而TLR9配体仅在IC31®或ODN1存在时才诱导I型IFN产生。此外，与IC31®长期孵育的moDCs相比，单独孵育24小时可显著提高IRF和IFN基因的表达。IC31®对IFN应答的佐剂活性显示是通过驻留在moDCs囊室中的tlr发挥的。基于这些结果，IC31®被确定为moDC调节佐剂，可调节NF-κB和IRF3介导的信号通路的平衡，以产生IFNβ。因此，在未来的疫苗接种策略中，IC31®作为一种有效的佐剂，可以增强对细胞内病原体和癌症的免疫应答。
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.
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DOI：
10.1038/nri3066
发表时间：
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期刊：
Nature reviews. Immunology
影响因子：
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作者：
通讯作者：
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