Role of BAFFR in antigen-specific B1b cell persistence

项目摘要。 传染病是世界范围内主要的死亡原因，接种疫苗是预防艾滋病的最有效手段 预防。接种疫苗导致对感染的长期抵抗力，这是由于产生了免疫性 记忆，对于记忆来说，大量抗原特异性B细胞的持续存在是必不可少的。规模的大小 记忆反应与抗原特异性记忆B细胞池的大小成正比。T细胞- 独立的B细胞反应比T细胞依赖的反应要快得多，并发挥着关键作用 在抗击各种感染方面，特别是由被包裹的细菌病原体引起的感染方面。纯正 从被包裹的细菌中分离出的多糖通常被称为T细胞非依赖性抗原 通过B细胞抗原受体交联化诱导一次抗体应答。这些抗原不会诱导 再次免疫后二次抗体反应增强，提示T细胞非依赖性 响应不会产生B细胞记忆。利用赫氏疏螺旋体感染，一种实验细菌系统 我们发现，除了其他免疫刺激途径外，它还参与B细胞抗原受体信号转导 B1B细胞在T细胞非依赖性B细胞存储器中的新功能。具体地说，我们发现B1B细胞扩张 与赫氏杆菌菌血症同时消退，并持续较长时间。B1B细胞来源 恢复期的小鼠而不是初出茅庐的小鼠会产生更高的抗体反应并产生免疫力， 这表明保护性反应对应于抗原特异性B1B细胞的扩增和持续，a B单元内存的关键属性。此外，使用表达多糖的阴沟肠杆菌 抗原，1-3葡聚糖已被证明，抗原特异性B1B细胞在早期阶段扩增 抗原相遇会持续很长时间，并在T细胞中产生强大的记忆反应- 以独立的方式。尽管这些细菌系统表明B1B细胞的记忆反应可以是 以T细胞不依赖的方式产生，支配长期维持的分子机制 内存B1B单元未知。B细胞激活因子(BAFF)，又称B淋巴细胞刺激因子 BLyS通过其受体BAFFR和TACI在成熟B细胞的存活和功能中发挥重要作用。 我们发现，在Hermsii感染系统中，有效的B细胞反应依赖于BAFF和BAFFR，但 不是TACI。此外，我们发现，对赫氏杆菌感染或感染做出反应而扩张并持续存在的B1B细胞 与未免疫的B1B细胞相比，阴沟肠杆菌免疫表达更高水平的BAFFR。因为更高水平的 B1B细胞上BAFFR的表达可以赋予BAFF依赖的竞争生存优势而不是单纯的B1B 在BAFF限制的条件下，我们假设细菌刺激的B1B细胞持续很长时间 通过BAFFR上调的期间。BAFFR在B1B长期维持中作用的确定 细胞将为生产有效的疫苗提供新的方法。

Project Summary. Infectious diseases are the leading cause of death worldwide and vaccination is the most effective means of prevention. Vaccination results in long-term resistance to infections due to the generation of immunological memory, for which persistence of high numbers of antigen-specific B cells is essential. The magnitude of anamnestic responses is directly proportional to the size of the antigen-specific memory B cell pool. T cell- independent B cell responses are much more rapid than the T cell-dependent responses and play a critical role in combating a variety of infections, in particular those caused by encapsulated bacterial pathogens. Pure polysaccharides isolated from encapsulated bacteria are commonly referred to as T cell-independent antigens and induce primary antibody responses by B cell antigen receptor cross-linking. These antigens do not induce heightened secondary antibody responses upon re-immunization, suggesting that T cell-independent responses do not generate B cell memory. Using Borrelia hermsii infection, an experimental bacterial system that engages B cell antigen receptor signaling in addition to other immunostimulatory pathways, we discovered a novel function for B1b cells in T cell-independent B cell memory. Specifically, we found that B1b cells expand concurrently with the resolution of B. hermsii bacteremia and persist for long time periods. B1b cells from convalescent mice but not from na¿ve mice generate a heightened antibody response and confer immunity, indicating that the protective response corresponds to antigen-specific B1b cell expansion and persistence, a key attribute of B cell memory. Additionally, using Enterobacter cloacae that expresses the polysaccharide antigen, ¿1-3 dextran it has been shown that antigen-specific B1b cells that expand in the initial phase of antigen encounter persist for long time periods and generate robust anamnestic responses in a T cell- independent manner. Although these bacterial systems demonstrate that B1b cell memory responses can be generated in a T cell-independent manner, the molecular mechanism governing the long-term maintenance of the memory B1b cells is unknown. B cell activating factor (BAFF), also known as B Lymphocyte Stimulator (BLyS) plays an important role in mature B cell survival and function through its receptors BAFFR and TACI. We found that in the B. hermsii infection system efficient B cell responses depend on BAFF and BAFFR but not TACI. Furthermore, we found that B1b cells that expand and persist in response to B. hermsii infection or E. cloacae immunization express higher levels of BAFFR compared to naive B1b cells. Since higher levels of BAFFR expression on B1b cells can impart a BAFF-dependent competitive survival advantage over naive B1b cells under BAFF-limited conditions, we hypothesize that bacteria-stimulated B1b cells persist for long time periods through BAFFR upregulation. Determination of the role of BAFFR in the long-term maintenance of B1b cells will provide novel approaches for the generation of effective vaccines.