Relationships between Tfh cells, somatic hypermutation, and the development of broadly neutralizing antibodies

项目摘要 关于产生HIV bnAb的细胞机制知之甚少。BnAb很难 发展并具有在生殖中心（GC）中广泛亲和力成熟的特征。一个假设是 GC中的Tfh细胞对于驱动HIV bnAb的发展是重要的。滤泡辅助性T细胞（Tfh） 是B细胞帮助的特化CD 4 T细胞，并且是GC所必需的和限制性的。(1)Tfh细胞如何 增强HIV bnAb的开发？是否与Tfh数量和/或选择功能有关？(2)身体怎么样 与bnAb发展的可能性相关的超突变？GC SHM活性是bnAb所必需的 发展，但是否存在数量关系？(3)哪些B细胞特征对bnAb至关重要 发展？我们假设HIV+患者中bnAb的产生可能主要依赖于（A） 不寻常的B细胞库特征，例如聚糖反应性;（B）特定类别的B细胞应答;和/或 (C)SHM探索的整体序列空间。

Project Summary Little is known about the cellular mechanisms involved in generating HIV bnAbs. BnAbs are very difficult to develop and have traits indicative of extensive affinity maturation in germinal centers (GC). One hypothesis is that Tfh cells in the GC are important for driving the development of HIV bnAbs. Follicular helper T cells (Tfh) are the specialized CD4 T cells for B cell help and are necessary and limiting for GCs. (1) How do Tfh cells enhance HIV bnAb development? Is it related to Tfh quantities and/or selective functions? (2) How is somatic hypermutation related to the likelihood of bnAb development? GC SHM activity is necessary for bnAb development, but is there a quantitative relationship? (3) What B cell characteristics are critical to bnAb development? We hypothesize that bnAb development in HIV+ patients may be primarily dependent on (A) unusual B cell repertoire features, such as glycan reactivity; (B) a particular category of B cell response; and/or (C) overall sequence space explored by SHM.