Molecular Regulation of Long-term Immune Memory

 描述(由申请人提供)：免疫记忆细胞的有效产生和长期维持是针对病原体的疫苗成功的关键。B细胞自噬缺陷的小鼠在免疫后表现出记忆B细胞维持的严重缺陷，并由于未能产生保护性二次抗体反应而死于病毒感染。自噬是记忆B细胞长期存在所必需的，以保护其免受病毒感染。同样，研究表明，自噬也是保护记忆T细胞所必需的。然而，自噬在保护记忆B细胞中的确切机制仍有待确定。我们发现，在线粒体自噬过程中，Nix和Bnip3这两个重要的Bcl2家族成员是产生抗原特异性记忆B细胞所必需的。我们假设自噬对于保护线粒体功能以保护记忆B细胞的生存和功能是必不可少的。我们将进行以下实验来验证这一假设：1)确定依赖NIX和Bnip3的线粒体自噬保护抗原特异性记忆B细胞的分子机制。在Nix和Bnip3缺陷的记忆B细胞中，线粒体自噬缺陷是否会导致代谢功能异常将被确定；2)检验线粒体自噬保护记忆B细胞免受细胞死亡的假设。线粒体完整性的破坏是否会导致记忆B细胞中线粒体重组体或DNA的释放，以及3)确定记忆B细胞中线粒体自噬的分子机制。新的Nix和Bnip3相互作用蛋白在调节线粒体自噬中的功能将被研究。这项研究的发现可能有助于开发更好的策略，通过靶向线粒体自噬来提高疫苗接种对感染的效果。

 DESCRIPTION (provided by applicant): Effective generation and long-term maintenance of immune memory cells are critical for the success of vaccines against pathogens. Mice with autophagy deficiency in B cells show a severe defect in the maintenance of memory B cells after immunization, and succumb to viral infections due to failure to generate protective secondary antibody responses. Autophagy is required for the long-term persistence of memory B cells to protect against viral infections. Similarly, it has been shown that autophagy is also required for the protection of memory T cells. However, the precise mechanisms for autophagy in the protection of memory B cells remain to be defined. We have found that Nix and Bnip3, two Bcl-2 family members important for mitochondrial autophagy, are required for the generation of antigen-specific memory B cells. We hypothesize that autophagy is essential for the protection of mitochondrial functions to protect the survival and functions of memory B cells. We will perform the following experiments to test this hypothesis: 1) To determine the molecular mechanisms by which Nix and Bnip3- dependent mitochondrial autophagy protects antigen-specific memory B cells. Whether defective mitochondrial autophagy in Nix- and Bnip3-deficient memory B cells leads to aberrant metabolic functions will be determined; 2) To test the hypothesis that mitochondrial autophagy protects against cell death in memory B cells. Whether disruption of mitochondrial integrity leads to the release of mitochondrial ptoteins or DNA in the induction of cell death in memory B cells; and 3) To determine the molecular mechanisms for mitochondrial autophagy in memory B cells. The functions of novel Nix- and Bnip3-interacting proteins in the regulation of mitochondrial autophagy will be studied. The findings from this study may facilitate the development of better strategies to enhance the efficacy of vaccination against infections by targeting mitochondrial autophagy.