Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
Laboratory of Lymphocyte Dynamics, The Rockefeller University, New York, NY 10065, USA.
Cell. 2023 Jan 5;186(1):147-161.e15. doi: 10.1016/j.cell.2022.11.032. Epub 2022 Dec 23.
Antibody responses are characterized by increasing affinity and diversity over time. Affinity maturation occurs in germinal centers by a mechanism that involves repeated cycles of somatic mutation and selection. How antibody responses diversify while also undergoing affinity maturation is not as well understood. Here, we examined germinal center (GC) dynamics by tracking B cell entry, division, somatic mutation, and specificity. Our experiments show that naive B cells continuously enter GCs where they compete for T cell help and undergo clonal expansion. Consistent with late entry, invaders carry fewer mutations but can contribute up to 30% or more of the cells in late-stage germinal centers. Notably, cells entering the germinal center at later stages of the reaction diversify the immune response by expressing receptors that show low affinity to the immunogen. Paradoxically, the affinity threshold for late GC entry is lowered in the presence of high-affinity antibodies.
抗体反应的特点是随着时间的推移亲和力和多样性不断增加。亲和力成熟发生在生发中心，其机制涉及多次体细胞突变和选择循环。抗体反应在进行亲和力成熟的同时如何多样化，还不是很清楚。在这里，我们通过跟踪 B 细胞进入、分裂、体细胞突变和特异性来检查生发中心（GC）的动态。我们的实验表明，幼稚 B 细胞不断进入生发中心，在那里它们竞争 T 细胞的帮助并进行克隆扩增。与晚期进入一致，入侵者携带的突变较少，但可贡献多达 30%或更多的晚期生发中心的细胞。值得注意的是，在反应后期进入生发中心的细胞通过表达对免疫原具有低亲和力的受体来使免疫反应多样化。矛盾的是，在高亲和力抗体存在的情况下，晚期 GC 进入的亲和力阈值降低。
