Role of BAFFR in antigen-specific B1b cell persistence

项目摘要。 传染病是全球死亡的主要原因，疫苗接种是预防和治疗传染病的最有效手段。 预防疫苗接种由于产生免疫原性抗体而导致对感染的长期抵抗。 记忆，其中大量抗原特异性B细胞的持续存在是必不可少的。的大小 记忆应答与抗原特异性记忆B细胞库的大小成正比。T细胞- 独立的B细胞应答比T细胞依赖性应答快得多，并且在免疫应答中起关键作用。 在对抗各种感染，特别是由包囊的细菌病原体引起的感染中。纯 从包囊细菌中分离的多糖通常被称为T细胞非依赖性抗原 并通过B细胞抗原受体交联诱导初级抗体应答。这些抗原不会诱导 再次免疫后的二次抗体应答增强，表明T细胞非依赖性 应答不产生B细胞记忆。使用赫氏疏螺旋体感染，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细胞抗原受体信号传导， B1 B细胞在T细胞非依赖性B细胞记忆中的新功能。具体地说，我们发现B1b细胞会扩张， 与B的决议同时进行。hermsii菌血症并持续很长时间。B1b细胞 恢复期小鼠而非未处理小鼠产生增强的抗体应答并赋予免疫力， 表明保护性应答对应于抗原特异性B1b细胞扩增和持续， B细胞存储器关键属性。另外，使用表达多糖的阴沟肠杆菌， 抗原，<$1 - 3葡聚糖已经表明，抗原特异性B1b细胞，扩大在初始阶段， 抗原接触持续很长时间，并在T细胞中产生强烈的记忆应答， 独立的方式。尽管这些细菌系统证明B1b细胞记忆反应可以被抑制， 产生的T细胞独立的方式，分子机制管理的长期维持， 记忆B1b单元是未知的。B细胞活化因子（BAFF），也称为B淋巴细胞刺激因子 （BLyS）通过其受体BAFFR和TACI在成熟B细胞存活和功能中起重要作用。 我们发现在B。hermsii感染系统有效B细胞应答依赖于BAFF和BAFFR， 不是泰慈此外，我们发现B1 B细胞对B的反应是扩增并持续存在。hermsii感染或 e.与初始B1b细胞相比，Cloblastin免疫表达更高水平的BAFFR。由于更高水平的 BAFFR在B1b细胞上的表达可以赋予BAFFR依赖的竞争性生存优势 细胞在BAFF限制条件下，我们假设细菌刺激的B1b细胞持续很长时间 通过BAFFR上调的时期。确定BAFFR在B1b长期维持中的作用 细胞将为产生有效疫苗提供新的方法。

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.