Alpha(v) integrins and germinal center B cell responses to viruses

项目摘要/摘要 更好地了解由各种类型的抗原触发的免疫信号机制对于 针对当前和新出现的病原体开发更有效的疫苗。我们的长期目标是 了解B细胞如何整合来自抗原及其环境的信号以产生有效的免疫 对抗病原体，同时保持对自体抗原的耐受性。 本申请的目的是确定一系列黏附分子， αv整合素和自噬蛋白调节生发中心(GC)B细胞对病毒抗原的处理 发展对流感病毒的有效免疫。在已发表的工作中，我们已经证明了αvβ3杂二聚体 来自αv家族，参与自噬途径的组成部分，以限制GC B细胞中的TLR信号，在 对含有TLR配体的病毒抗原的反应。结果，αv-CD19小鼠在B细胞上缺乏αv，显示 GC介导的抗体反应的关键特征增加，如亲和力成熟、记忆生成 B细胞和长寿浆细胞，在病毒样颗粒或流感病毒免疫后。此外， 这些小鼠对多种流感病毒株产生更强的交叉反应抗体 用一个菌株免疫，对异亚型菌株也产生更好的交叉保护免疫力。αv- CD19小鼠的自身抗体也随着年龄的增长而增加，我们认为αv介导的对TLR的调节 信号传递是一种限制B细胞对自身抗原过度反应的机制。我们对此的中心假设 Grant，是αv-自噬途径也调节含有tlr的抗原的内体处理。 来自病毒的配体，限制这些抗原对GC B细胞的激活。删除此控件 从B细胞，增强GC B细胞TLR信号和GC介导的抗体的产生 多种病毒株可产生更好的交叉保护免疫力。在这笔赠款中，我们建议：(1)确定 通过去除αv-自噬途径增强GC反应的机制导致更好的交叉反应。 对流感病毒株的保护性免疫；(2)确定是否可以使用药物靶向 这一途径来操纵对流感病毒的免疫反应；以及(3)确定病毒抗原是如何 由GC B细胞处理，以及αv自噬途径如何改变这一过程。我们提出这项建议的理由是 更好地了解病毒抗原调节GC B细胞激活的新途径将使我们能够 制定急需的疫苗接种策略，以产生有效的抗病毒免疫。 这项拟议的工作意义重大，因为它解决了GC B细胞激活如何影响 广泛保护性抗病毒免疫，了解这一点对于开发更好的疫苗至关重要。此外， 在这些研究的基础上，αv拮抗剂可用于设计疫苗佐剂，以提供长期的 对多种流感病毒株的保护。我们的方法是创新的，因为我们使用了独特的 增强B细胞TLR信号的小鼠模型以研究一种新的TLR-αv-自噬途径。

Project Summary/Abstract A better understanding of immune signaling mechanisms triggered by various types of antigens is critical for development of more effective vaccines against current and emerging pathogens. Our long-term goal is to understand how B cells integrate signals from antigens and their environment to produce effective immunity against pathogens while maintaining tolerance to self-derived antigens. The objective in this application is to determine the mechanisms by which a family of adhesion molecules, αv integrins and autophagy proteins regulate germinal center (GC) B cell processing of viral antigens and development of effective immunity to Influenza virus. In published work, we have shown that αvβ3 heterodimer from the αv family, engages components of the autophagy pathway, to limit TLR signaling in GC B cells, during response to viral antigens containing TLR ligands. As a result, αv-CD19 mice, lacking αv on B cells show increase in key features of GC-mediated antibody response such as affinity maturation, generation of memory B cells and long-lived plasma cells, upon immunization with virus like particles or Influenza virus. Moreover, these mice develop increased cross-reactive antibodies against multiple influenza virus strains after immunization with one strain and also develop better cross-protective immunity to heterosubtypic strains. αv- CD19 mice also develop increased autoantibodies with age, and we propose that αv-mediated regulation of TLR signaling is a mechanism that limits excessive B cell responses to self-antigens. Our central hypothesis for this grant, is that the αv-autophagy pathway also regulates endosomal processing of antigens containing TLR ligands, that are derived from viruses, and limits GC B cell activation by these antigens. Removal of this control from B cells, enhances GC B cell TLR signaling and GC-mediated generation of antibodies reactive against multiple strains of viruses leading to better cross-protective immunity. In this grant we propose to: (1) Determine the mechanism by which augmenting GC reactions by removal of αv-autophagy pathway leads to better cross- protective immunity to influenza virus strains; (2) Determine whether we can use pharmacological targeting of this pathway to manipulate immune responses to influenza virus; and (3) Determine how viral antigens get processed by GC B cells and how αv-autophagy pathway alter this process. Our rationale for this proposal is that a better understanding of new pathways regulating GC B cell activation by viral antigens will allow us to develop much needed vaccination strategies for generation of effective anti-viral immunity. The proposed work is significant because it addresses the mechanisms of how GC B cell activation affects broadly protective anti-viral immunity, which is essential to understand for developing better vaccines. Moreover, based on these studies, αv antagonists could be used to design vaccine adjuvants that provide long-term protection against wide variety of Influenza virus strains. Our approach is innovative as we are using a unique mouse model of enhanced B cell TLR signaling to investigate a novel TLR-αv-autophagy pathway.