REGULATION OF B CELL MEMORY

记忆B细胞通过淋巴细胞中的特化途径分化 它是一个独立的，不同于， 抗体形成，包括体细胞突变和选择 对抗原具有高亲和力的细胞。GC/内存的调节 途径，它代表了最重要的适应性免疫机制， 是很难理解的。这项提案将测试三个新颖的想法， 这个规定。第一，假设B细胞的GC/记忆通路 分化由特化的辅助T细胞（TH）亚群驱动。 这些TH将通过细胞分选和细胞克隆来分离，并且它们的 将在体内研究过继后的性质和作用机制。 转移到用半抗原免疫的B细胞重建的scid小鼠中， 载体结合物。老年中心（GC）的发展 将通过免疫组织化学技术监测脾脏， 测定半抗原特异性血清抗体的亲和力。的 GC B细胞中的体细胞超突变活性将通过 编码H链的重排VDJ片段的序列分析 半抗原特异性抗体第二，提出GC/内存响应 可以用抗原（Ag）与抗体的复合物选择性地刺激 （Ab）。该假设将使用已知的定义明确的Ab进行检验。 同种型和亲和性以及Ag/Ab复合物活性的机制 结合特定TH亚群和克隆提供的帮助， 被研究。第三，提出确定存储器B是否 细胞回到骨髓，这似乎是一个主要的网站， 记忆性抗体应答以及骨髓环境是否有助于 到一个额外的分子和功能成熟的回忆 抗体库拟议的研究将阐明重要的 免疫记忆的机制，提供了操纵免疫记忆的工具。 适应性免疫反应，并提出新的疫苗接种策略。

Memory B cells differentiate via a specialized pathway in the lymphoid germinal centers (GC) which is different from, and independent of the antibody formation and which includes somatic mutation and selections of cells with high affinity for the antigen. The regulation of the GC/memory pathway, which represents the most important adaptive immune mechanism, is poorly understood. This proposal will test three novel ideas about this regulation. One, it is postulated that GC/memory pathway of B cell differentiation is driven by specialized helper T cell (TH) subsets. These TH will be isolated by cell sorting and cellular cloning and their properties and mechanisms of action will be studied in vivo upon adoptive transfer into B cell-reconstituted scid mice immunized with hapten- carrier conjugates. The development of germinal centers (GC) in the spleen will be monitored by immunohistochemical techniques and the affinities of hapten-specific serum antibodies will be determined. The somatic hypermutation activity in the GC B cells will be studied by the sequence analysis of the rearranged VDJ segments that encode the H chains of hapten-specific Ab. Second, it is proposed that the GC/memory response may selectively stimulated with complexes of antigen (Ag) with antibody (Ab). This hypothesis will be tested using well-defined Ab of known isotype and affinity and the mechanism of the Ag/Ab complex activity in conjunction with the help provided by specific TH subsets and clones will be studied. Thirdly, it is proposed to determine whether the memory B cells home to bone marrow which appears to be a major site of the anamnestic Ab response and whether the bone marrow environment contribute to an additional molecular and functional maturation of the anamnestic antibody repertoire. The proposed studies will elucidate important mechanisms of immunological memory, provide tools for manipulation of the adaptive immune response and suggest novel strategies for vaccination.