Molecular Regulation of Long-term Immune Memory

 描述（由申请方提供）：免疫记忆细胞的有效产生和长期维持对于疫苗成功对抗病原体至关重要。在B细胞中具有自噬缺陷的小鼠在免疫接种后在记忆B细胞的维持方面显示出严重缺陷，并且由于不能产生保护性二次抗体应答而使B死于病毒感染。自噬是记忆B细胞长期存活以抵御病毒感染所必需的。类似地，已经表明自噬也是保护记忆T细胞所必需的。然而，自噬保护记忆B细胞的确切机制仍有待确定。我们已经发现，Nix和Bnip 3，两个Bcl-2家族成员的线粒体自噬的重要性，所需的抗原特异性记忆B细胞的产生。我们假设自噬对于保护线粒体功能以保护记忆B细胞的存活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Nix和Bnip 3依赖的线粒体自噬保护抗原特异性记忆B细胞的分子机制。将确定Nix和Bnip 3缺陷型记忆B细胞中缺陷型线粒体自噬是否导致异常代谢功能; 2）检验线粒体自噬防止记忆B细胞中细胞死亡的假设。在记忆B细胞中，线粒体完整性的破坏是否导致线粒体蛋白或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。将研究新型Nix和Bnip 3相互作用蛋白在线粒体自噬调节中的功能。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有效性。

 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.