Chen Jingjing, Cai Zhenming, Zhang Le, Yin Yuye, Chen Xufeng, Chen Chao, Zhang Yang, Zhai Sulan, Long Xuehui, Liu Xiaolong, Wang Xiaoming
Department of Immunology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; and.
State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
J Immunol. 2017 Jun 1;198(11):4304-4311. doi: 10.4049/jimmunol.1700159. Epub 2017 Apr 26.
The germinal center (GC) is the site where activated B cells undergo rapid expansions, somatic hypermutation, and affinity maturation. Affinity maturation is a process of Ag-driven selection. The amount of Ag acquired and displayed by GC B cells determines whether it can be positively selected, and therefore Ag acquisition has to be tightly regulated to ensure the efficient affinity maturation. Cell expansion provides sufficient quantity of GC B cells and Abs, whereas affinity maturation improves the quality of Abs. In this study, we found that Lis1 is a cell-intrinsic regulator of Ag acquisition capability of GC B cells. Lack of Lis1 resulted in redistribution of polymerized actin and accumulation of F-actin at uropod; larger amounts of Ags were acquired and displayed by GC B cells, which presumably reduced the selection stringency. Affinity maturation was thus compromised in Lis1-deficient mice. Consistently, overexpression of Lis1 in GC B cells led to less Ag acquisition and display. Additionally, Lis1 is required for GC B cell expansion, and Lis1 deficiency blocked the cell cycle at the mitotic phase and GC B cells were prone to apoptosis. Overall, we suggest that Lis1 is required for GC B cell expansion, affinity maturation, and maintaining functional intact GC response, thus ensuring both the quantity and quality of Ab response.
生发中心（GC）是活化B细胞进行快速增殖、体细胞超突变和亲和力成熟的场所。亲和力成熟是一个由抗原驱动的选择过程。GC B细胞获取和展示的抗原量决定了其是否能被阳性选择，因此必须严格调控抗原获取以确保有效的亲和力成熟。细胞增殖提供了足够数量的GC B细胞和抗体，而亲和力成熟则提高了抗体的质量。在本研究中，我们发现Lis1是GC B细胞抗原获取能力的细胞内在调节因子。Lis1的缺失导致聚合肌动蛋白重新分布以及F-肌动蛋白在尾足处积累；GC B细胞获取和展示了大量抗原，这可能降低了选择的严格性。因此，Lis1缺陷小鼠的亲和力成熟受到损害。同样，在GC B细胞中过表达Lis1导致抗原获取和展示减少。此外，Lis1是GC B细胞增殖所必需的，Lis1缺陷会在有丝分裂期阻断细胞周期，并且GC B细胞易于凋亡。总体而言，我们认为Lis1是GC B细胞增殖、亲和力成熟以及维持功能性完整的GC反应所必需的，从而确保抗体反应的数量和质量。
