Adaptive immunity involves the development of bespoke antibodies in germinal centers (GCs) through immunoglobulin somatic hypermutation (SHM) in GC dark zones (DZs) and clonal selection in light zones (LZs). Accurate selection requires that cells fully replace surface B cell receptors (BCRs) following SHM, but whether this happens before LZ entry is not clear. We found that most GC B cells degrade pre-SHM receptors before leaving the DZ, and that B cells acquiring crippling mutations during SHM rarely reached the LZ. Instead, apoptosis was triggered preferentially in late G1, a stage wherein cells with functional BCRs re-entered cell cycle or reduced surface expression of the chemokine receptor CXCR4 to enable LZ migration. Ectopic expression of the anti-apoptotic gene Bcl2 was not sufficient for cells with damaging mutations to reach the LZ, suggesting that BCR-dependent cues may actively facilitate the transition. Thus, BCR replacement and pre-screening in DZs prevents the accumulation of clones with non-functional receptors and facilitates selection in the LZ.

适应性免疫涉及通过 GC 暗区 (DZ) 中的免疫球蛋白体细胞超突变 (SHM) 和亮区 (LZ) 中的克隆选择，在生发中心 (GC) 中开发定制抗体。准确的选择需要细胞在 SHM 后完全取代表面 B 细胞受体 (BCR)，但这是否发生在 LZ 进入之前尚不清楚。我们发现大多数 GC B 细胞在离开 DZ 之前会降解前 SHM 受体，并且在 SHM 期间获得严重突变的 B 细胞很少到达 LZ。相反，细胞凋亡优先在 G1 晚期触发，在这一阶段，具有功能性 BCR 的细胞重新进入细胞周期或降低趋化因子受体 CXCR4 的表面表达以实现 LZ 迁移。抗凋亡基因Bcl2的异位表达具有破坏性突变的细胞不足以到达 LZ，这表明依赖 BCR 的线索可能会积极促进转变。因此，DZ 中的 BCR 替代和预筛选可防止具有非功能性受体的克隆积累，并促进 LZ 中的选择。