Spatiotemporal dynamics of Bach2 orchestrates B cell responses and fate decision

The molecular circuits that direct early T-dependent B cell responses and alternative cell-fate decisions remain poorly understood. Here, we show that either B cell receptor (BCR) or CD40 signals promoted mTORC1-dependent translation of the transcription factor Bach2. Transient up-regulation of Bach2 protein restrained activated B cell expansion and differentiation into plasma cell while promoting the germinal center (GC) and memory B cell fates at the pre-GC stage. However, enforced Bach2 expression facilitated memory B cell generation versus other cell fates. Mechanistically, Bach2 limited access of AP-1 factors and formed a reciprocal repression loop with IRF4. BCR and CD40 signals also down-regulated Bach2 transcript in antigen-activated B cells, and diversified its abundance in various effector populations, predisposing Bach2 protein expression and subsequent cell-fate choices during memory recall and GC reaction. Thus signaling-induced differential dynamics of Bach2 protein and mRNA in activated B cell control their cell-fate outcomes and imprint the fate of their descendant effector cells. Overall design: To gain insight into the suppressive functions of Bach2 on PC differentiation, Bach2-sufficient and deficient CD19+IgD-GL7+CD38+ activated NP-specific B cells were sorted at day 2 after immunization and subjected for transcriptional profile analysis

指导早期T细胞依赖型B细胞应答与替代性细胞命运抉择的分子环路，迄今尚未得到充分阐释。本研究证实，B细胞受体（B cell receptor, BCR）或CD40信号均可促进转录因子Bach2的雷帕霉素复合物1（mTORC1）依赖型翻译。Bach2蛋白的瞬时上调可抑制活化B细胞的扩增及其向浆细胞的分化，同时在生发中心前阶段促进细胞向生发中心（GC）与记忆B细胞的命运定向。然而，过表达Bach2则相较于其他细胞命运，更易促进记忆B细胞的生成。机制层面而言，Bach2可限制AP-1转录因子家族的结合，并与干扰素调节因子4（IRF4）形成相互抑制环路。BCR与CD40信号同时还可在抗原活化的B细胞中下调Bach2的转录本，并在各类效应细胞群中使其丰度呈现差异化，进而调控Bach2蛋白表达与后续细胞命运选择，影响记忆再次应答与生发中心反应过程中的细胞命运抉择。综上，信号诱导的活化B细胞中Bach2蛋白与mRNA的差异动态变化，决定了细胞的命运结局，并对子代效应细胞的命运产生印记。整体实验设计：为深入解析Bach2对浆细胞分化的抑制功能，我们于免疫后第2天分选得到Bach2充足与缺失的CD19+IgD-GL7+CD38+活化NP特异性B细胞，并对其开展转录组分析。