PDF(Pubmed)
Abstract：
Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation prevents TFEB-driven cell death, while enhancing and prolonging TFEB\'s nuclear residency, which hallmarks antigenic experience also of memory B cells. In mice, TFEB shapes the transcriptional landscape of germinal center B cells. Within the germinal center, TFEB facilitates the dark zone entry of light-zone-residing centrocytes through regulation of chemokine receptors and, by balancing the expression of Bcl-2/BH3-only family members, integrates antigen-induced apoptosis with T cell-provided CD40 survival signals. Thus, TFEB reprograms antigen-primed germinal center B cells for cell fate decisions.
摘要：
B细胞抗原受体(BCR)的连接启动体液免疫。然而,没有适当共刺激的BCR信号使B细胞死亡而不是分化成免疫效应细胞。BCR激活如何耗尽潜在的自身反应性B细胞，同时启动从同源T淋巴细胞接受拯救和分化信号仍然未知。这里,我们使用基于质谱的蛋白质组学方法来鉴定胞质/核穿梭元件，并揭示转录因子EB（TFEB）作为驱动激活诱导的细胞凋亡的中央BCR控制变阻器，并通过支持B细胞迁移和抗原呈递同时促进共刺激拯救信号的接收。CD40共刺激可防止TFEB驱动的细胞死亡，在增强和延长TFEB的核停留时间的同时，这标志着记忆B细胞的抗原经历。在老鼠身上,TFEB塑造生发中心B细胞的转录景观。在生发中心内，TFEB通过调节趋化因子受体促进光区中心细胞的暗区进入，通过平衡Bcl-2/BH3-only家族成员的表达，整合抗原诱导的细胞凋亡与T细胞提供的CD40存活信号。因此，TFEB重新编程抗原引发的生发中心B细胞以决定细胞命运。
