Intra-and inter-cellular vaccine-induced signaling pathways

最佳的疫苗效果不仅需要保护性抗原，还需要强免疫激活剂作为佐剂。大多数病毒疫苗，如流感疫苗和非病毒基因疫苗(如：例如，DNA疫苗)，含有核酸，它似乎是必不可少的“内置”佐剂。特异性受体，包括toll样受体（TLR）、视黄酸诱导蛋白I（RIG-I）样受体（RLR）和核苷酸结合寡聚结构域（NOD）样受体（NLR），可以检测特定的核酸模式，如序列、结构和修饰，这些模式也受免疫组织、细胞类型和细胞内定位的影响。由此产生的免疫激活受到细胞内和细胞间信号通路的独特调节，这对于随后的疫苗免疫原性（如抗原特异性t细胞和b细胞反应）是必不可少的。针对甲型H1N1流感病毒感染有多种疫苗组合；然而，控制其免疫原性的更多机制尚不清楚。在这里，我们发现浆细胞样树突状细胞（pDC）及其i型ifn介导的细胞内和细胞间信号传导对于在灭活病毒粒子接种后诱导病毒特异性CD4 T和B细胞至关重要。虽然toll样受体（TLR） 7介导了活病毒粒子疫苗和灭活病毒粒子疫苗的免疫原性，但rig - i -like或nod -like受体没有介导，一种常用的分裂疫苗未能激活TLR7，导致在幼稚小鼠中无效。在小鼠中，pdc -激活佐剂恢复了分裂疫苗的免疫原性，但单独的分裂疫苗足以唤起人类的记忆反应，这强调了pdc - tlr7 /9- 1型轴对启动的重要性，而不是继发性免疫。铝基佐剂（明矾）广泛用于人类疫苗接种，尽管对其作用机制知之甚少。在这里，我们报道，在小鼠中，明矾引起宿主细胞DNA的释放，这是一种有效的内源性免疫刺激信号，介导明矾佐剂活性。此外，我们发现宿主DNA信号在明矾免疫后对IgE和IgG1的产生有差异调节。事实上，我们支持宿主DNA通过IRF-3独立机制诱导原代B细胞反应，包括IgG1的产生，以及通过IRF-3依赖机制诱导与IgE同型转换和效应组织反应相关的炎性“典型”2型T细胞反应。宿主细胞DNA是一种传递明矾佐剂活性的损伤相关分子模式，这一发现可能有助于理解当前疫苗的作用机制和设计新的佐剂。奥史等。对病毒感染和疫苗接种的先天和适应性免疫反应。流行病毒学报，2011,1(4):226-232.2。Marichal等人。濒死宿主细胞释放的DNA介导铝佐剂活性。中华医学杂志，2011(8):996-10023。等。浆细胞样树突状细胞描述流感疫苗亚型的免疫原性。科学学报，2010,32(5):563 - 567。少

Optimal vaccine efficacy requires not only a protective antigen, but also a strong immune activator as an adjuvant. Most viral vaccines, such as influenza vaccines and non-viral genetic vaccines(e. g., DNA vaccines), contain nucleic acids, which appear to act as essential "built-in" adjuvants. Specific receptors, including toll-like receptors(TLR), retinoic-acid-inducible protein I(RIG-I)-like receptors(RLR), and nucleotide-binding oligomerization domain(NOD)-like receptors(NLR), can detect specific nucleic acid patterns, such as sequence, structure and modification, which are also influenced by the immunized tissue, cell type, and intracellular localization. The resultant immune activation is uniquely regulated by intra-and inter-cellular signaling pathways, which are indispensable for the ensuing vaccine immunogenicity, such as antigen-specific T-and B-cell responses.A variety of vaccine compositions for H1N1 influenza A virus infections are available ; however, the key innate immune … More mechanisms controlling their immunogenicity remain unclear. Here we identified that plasmacytoid dendritic cells(pDC) and their type-I IFN-mediated intra-and inter-cellular signalling were essential for the induction of virus specific CD4 T and B cells following killed virion vaccination. While Toll-like receptor(TLR) 7, but not RIG-I-like-or NOD-like-receptors, mediated immunogenicity of both live and killed virion vaccines, a commonly used split vaccine failed to activate TLR7, resulting in no efficacy in naive mice. PDC-activating adjuvant restored split vaccine immunogenicity in mice, but split vaccine alone was sufficient to recall memory responses in humans, underscoring the importance of the pDC-TLR7/9-type-I axis for priming, but not secondary immunization.Aluminum-based adjuvants(alum) are widely used in human vaccination, although little is understood of their mechanisms of action. Here, we report that, in mice, alum causes the release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we show that host DNA signaling differentially regulates IgE and IgG1 production upon alum immunization. Indeed, we show support that host DNA induces primary B cell responses, including IgG1 production, through IRF-3 independent mechanisms, and inflammatory'canonical' type 2 T cell responses associated with IgE isotype switching and effector tissue responses through IRF-3 dependent mechanisms. The finding that host cell DNA is a damage-associated molecular pattern relaying alum adjuvant activity may thus help in the comprehension of the mechanisms of action of current vaccines and in the design of novel adjuvants.1.Aoshi T et al. Innate and adaptive immune responses to viral infection and vaccination. Curr Opin Virol. 2011, 1(4): 226-232.2.Marichal T et al. DNA released from dying host cells mediates aluminum adjuvant activity. Nat. Med. 2011 17(8): 996-10023.Koyama S, et al. Plasmacytoid dendritic cells delineate immunogenicity of influenza vaccine subtypes. Sci Transl Med. 2010 2(25): 25ra24. Less