表观遗传记录史揭示BLIMP1-BACH的2平衡决定记忆B细胞再激活的分化命运，这一成果由清华大学祁海、山西医科大学史文娟研究团队经过不懈努力而取得。2024年7月5日出版的《自然—免疫学》杂志发表了这一最新研究成果。

据了解，记忆B细胞(MBCs)在抗原回忆过程中分化为浆细胞(PCs)或生发中心(GCs)。这个决定是如何被编程的还不清楚。

该研究团队发现在初级反应过程中，两个拮抗转录因子——B淋巴细胞诱导的成熟蛋白1（BLIMP1）和BTB结构域和CNC同源物2（BACH2）之间的相对强度逐渐增加，倾向于BLIMP1，在抗原反应的B细胞中占据优势。优先产生继发性生发中心的记忆B细胞亚群比易发生浆细胞的亚群表达较高的BACH2，但较低的BLIMP1。在命运易感的记忆B细胞亚群中，改变BLIMP1-BACH2的平衡可能会改变他们的命运偏好。

在BLIMP1-BACH2平衡变化的基础上，研究团队观察到浆细胞中特异性打开的染色质位点的可及性逐渐增加，特别是那些含有干扰素敏感反应元件(ISREs)并由干扰素调节因子4 (IRF4)控制的染色质位点。IRF4通过B细胞受体、CD40或先天受体信号传导上调，并根据刺激强度诱导不同水平的浆细胞特异性表观遗传印迹。

通过分析历史标记的生发中心B细胞，该团队发现随着时间的推移，浆细胞特异性的IRF4控制基因位点的染色质可及性逐渐增加。因此，B细胞的累积刺激史以IRF4依赖的方式被表观遗传记录下来，决定了BLIMP1和BACH2在个体记忆B细胞中的相对强度，并决定了它们在再刺激后发展为生发中心或浆细胞的概率。

附：英文原文

Title: Epigenetic recording of stimulation history reveals BLIMP1–BACH2 balance in determining memory B cell fate upon recall challenge

Author: Shao, Wen, Wang, Yifeng, Fang, Qian, Shi, Wenjuan, Qi, Hai

Issue&Volume: 2024-07-05

Abstract: Memory B cells (MBCs) differentiate into plasma cells (PCs) or germinal centers (GCs) upon antigen recall. How this decision is programmed is not understood. We found that the relative strength between two antagonistic transcription factors, B lymphocyte-induced maturation protein 1 (BLIMP1) and BTB domain and CNC homolog 2 (BACH2), progressively increases in favor of BLIMP1 in antigen-responding B cells through the course of primary responses. MBC subsets that preferentially produce secondary GCs expressed comparatively higher BACH2 but lower BLIMP1 than those predisposed for PC development. Skewing the BLIMP1–BACH2 balance in otherwise fate-predisposed MBC subsets could switch their fate preferences. Underlying the changing BLIMP1-over-BACH2 balance, we observed progressively increased accessibilities at chromatin loci that are specifically opened in PCs, particularly those that contain interferon-sensitive response elements (ISREs) and are controlled by interferon regulatory factor 4 (IRF4). IRF4 is upregulated by B cell receptor, CD40 or innate receptor signaling and it induces graded levels of PC-specifying epigenetic imprints according to the strength of stimulation. By analyzing history-stamped GC B cells, we found progressively increased chromatin accessibilities at PC-specific, IRF4-controlled gene loci over time. Therefore, the cumulative stimulation history of B cells is epigenetically recorded in an IRF4-dependent manner, determines the relative strength between BLIMP1 and BACH2 in individual MBCs and dictates their probabilities to develop into GCs or PCs upon restimulation.

DOI: 10.1038/s41590-024-01900-2

Source: https://www.nature.com/articles/s41590-024-01900-2