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

项目摘要 人们对产生HIV bNAbs的细胞机制知之甚少。BNAbs很难检测到 在生发中心(GC)发育并具有广泛亲和力成熟的特征。一种假设是 GC中的TFH细胞对于驱动HIV bNAbs的发展是重要的。滤泡辅助T细胞(TFH) 特化的CD4T细胞对B细胞有帮助，对GC是必要的和有限的。(1)TFH细胞是如何 加强艾滋病毒bNab的开发？它与TFH的数量和/或选择功能有关吗？(2)体细胞是如何 高突变与bNab发生的可能性有关？BNab需要GC SHM活动 发育，但有数量关系吗？(3)B细胞的哪些特性对bNab至关重要 发展？我们假设HIV+患者中bNab的发育可能主要依赖于(A) 不寻常的B细胞谱系特征，例如糖链反应性；(B)特定类别的B细胞反应；和/或 (C)SHM探索的整体层序空间。

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.