Intra-and inter-cellular vaccine-induced signaling pathways

最佳的疫苗效力不仅需要保护性抗原，还需要强大的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DNA疫苗)，都含有核酸，它们似乎是必不可少的“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)和核苷酸结合寡聚化结构域(NOD)样受体(NLR)，它们可以检测特定的核酸模式，如序列、结构和修饰，这些模式还受到免疫组织、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，这些通路对于随后的疫苗免疫原性是不可或缺的，例如抗原特异性T细胞和B细胞反应。针对H1N1流感病毒感染的疫苗组合物有多种；然而，关键的先天免疫…更多控制其免疫原性的机制尚不清楚。在此，我们发现浆细胞样树突状细胞(PDC)及其I型干扰素介导的细胞内和细胞间信号转导对于灭活病毒疫苗后病毒特异性CD4T和B细胞的诱导是必不可少的。虽然Toll样受体(TLR)7，而不是Rig-I样受体或Nod样受体，介导了活疫苗和灭活病毒疫苗的免疫原性，但常用的裂解疫苗未能激活TLR7，导致对幼鼠无效。PDC激活佐剂恢复了裂解疫苗在小鼠的免疫原性，但裂解疫苗本身就足以回忆人类的记忆反应，强调了PDC-TLR7/9-I型轴对启动而不是二次免疫的重要性。铝佐剂(明矾)被广泛用于人类疫苗接种，尽管人们对其作用机制知之甚少。在这里，我们报告，在小鼠中，明矾引起宿主细胞DNA的释放，这是一种强大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信号对明矾免疫后的IgE和IgG1的产生有不同的调节作用。事实上，我们支持宿主DNA通过IRF-3非依赖机制诱导初级B细胞反应，包括产生IgG1，以及通过IRF-3依赖机制诱导与IgE同型转换相关的炎症性“规范”2型T细胞反应和效应组织反应。宿主细胞DNA是一种损伤相关的分子模式，继而影响明胶佐剂的活性，这一发现可能有助于理解当前疫苗的作用机制，并有助于设计新的佐剂。针对病毒感染和疫苗接种的先天和获得性免疫反应。科尔·奥宾·维罗尔。2011，1(4)：226-232.2.Marichal T et al.死亡宿主细胞释放的DNA介导铝佐剂活性。纳特。地中海医院。2011年17(8)：996-10023.小山，S，等.浆细胞样树突状细胞描述流感疫苗亚型的免疫原性。SCI，Transl Med.2010年2(25)：25：24。较少

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