Department of Cell and Developmental Biology, Northwestern University, Chicago, IL, USA.
Center for Human Immunobiology, Northwestern University, Chicago, IL, USA.
Nat Immunol. 2024 Sep;25(9):1704-1717. doi: 10.1038/s41590-024-01920-y. Epub 2024 Aug 14.
The mammalian Brg1/Brm-associated factor (BAF) complexes are major regulators of nucleosomal remodeling that are commonly mutated in several cancers, including germinal center (GC)-derived B cell lymphomas. However, the specific roles of different BAF complexes in GC B cell biology are not well understood. Here we show that the AT-rich interaction domain 1a (Arid1a) containing canonical BAF (cBAF) complex is required for maintenance of GCs and high-affinity antibody responses. While Arid1a-deficient B cells undergo initial activation, they fail to sustain the GC program. Arid1a establishes permissive chromatin landscapes for B cell activation and is concomitantly required to suppress inflammatory gene programs. The inflammatory signatures instigated by Arid1a deficiency promoted the recruitment of neutrophils and inflammatory monocytes. Dampening of inflammatory cues through interleukin-1β blockade or glucocorticoid receptor agonist partially rescued Arid1a-deficient GCs, highlighting a critical role for inflammation in impeding GCs. Our work reveals essential functions of Arid1a-dependent cBAF in promoting efficient GC responses.
哺乳动物中的 Brg1/Brm 相关因子 (BAF) 复合物是核小体重塑的主要调节因子，在包括生发中心 (GC) 衍生的 B 细胞淋巴瘤在内的几种癌症中经常发生突变。然而，不同 BAF 复合物在 GC B 细胞生物学中的具体作用尚不清楚。在这里，我们表明富含 AT 的相互作用结构域 1a（Arid1a）的经典 BAF（cBAF）复合物对于维持 GC 和高亲和力抗体反应是必需的。虽然 Arid1a 缺陷的 B 细胞经历了初始激活，但它们无法维持 GC 程序。Arid1a 为 B 细胞激活建立了允许性染色质景观，并且同时需要抑制炎症基因程序。由 Arid1a 缺陷引发的炎症特征促进了中性粒细胞和炎症性单核细胞的募集。通过白细胞介素 1β 阻断或糖皮质激素受体激动剂抑制炎症信号部分挽救了 Arid1a 缺陷的 GC，突出了炎症在阻碍 GC 中的关键作用。我们的工作揭示了 Arid1a 依赖性 cBAF 在促进有效 GC 反应中的重要功能。
