Abraham Ajay, Samaniego-Castruita Daniela, Paladino Jillian, Han Isabella, Ramesh Prathyaya, Tran Mi Thao, Southern Rebecca M, Shukla Ashima, Shukla Vipul
Department of Cell and Developmental Biology, Northwestern University, Chicago, Illinois, USA, 60611.
Center for Human Immunobiology, Northwestern University, Chicago, Illinois, USA, 60611.
Res Sq. 2024 Jan 18:rs.3.rs-3871185. doi: 10.21203/rs.3.rs-3871185/v1.
Differentiating B cells in germinal centers (GC) require tightly coordinated transcriptional and epigenetic transitions to generate efficient humoral immune responses. The mammalian Brg1/Brm-associated factor (BAF) complexes are major regulators of nucleosomal remodeling, crucial for cellular differentiation and development, and are commonly mutated in several cancers, including GC-derived B cell lymphomas. However, the specific roles of distinct BAF complexes in GC B cell biology and generation of functional humoral immune responses are not well understood. Here, we show that the A-T Rich Interaction Domain 1a (Arid1a) containing canonical BAF (cBAF) complex is required for maintenance of GCs and therefore high affinity antibody responses. While Arid1a-deficient B cells undergo activation to initiate GC responses, they fail to sustain the GC program resulting in premature GC collapse. We discovered that Arid1a-dependent cBAF activity establishes permissive chromatin landscapes during B cell activation and is concomitantly required to suppress inflammatory gene programs to maintain transcriptional fidelity in early GC B cells. Interestingly, the inflammatory signatures instigated by Arid1a deficiency in early GC B cells recruited neutrophils and inflammatory monocytes and eventually disrupted GC homeostasis. Dampening of inflammatory cues with anti-inflammatory glucocorticoid receptor signaling rescued GC B cell differentiation of Arid1a-deficient B cells, thus highlighting a critical role of inflammation in impeding GC responses. In sum, our work identifies essential functions of Arid1a-dependent BAF activity in promoting efficient GC responses. These findings further support an emerging paradigm in which unrestrained inflammation limits GC-derived humoral responses, as reported in the context of severe bacterial and viral infections.
生发中心（GC）中的B细胞分化需要紧密协调的转录和表观遗传转变，以产生有效的体液免疫反应。哺乳动物的Brg1/Brm相关因子（BAF）复合物是核小体重塑的主要调节因子，对细胞分化和发育至关重要，并且在包括GC衍生的B细胞淋巴瘤在内的几种癌症中普遍发生突变。然而，不同的BAF复合物在GC B细胞生物学和功能性体液免疫反应产生中的具体作用尚不清楚。在这里，我们表明，含有典型BAF（cBAF）复合物的富含AT相互作用结构域1a（Arid1a）是维持生发中心所必需的，因此也是高亲和力抗体反应所必需的。虽然缺乏Arid1a的B细胞会被激活以启动生发中心反应，但它们无法维持生发中心程序，导致生发中心过早崩溃。我们发现，依赖Arid1a的cBAF活性在B细胞激活过程中建立了允许的染色质景观，并且同时需要抑制炎症基因程序，以维持早期GC B细胞中的转录保真度。有趣的是，早期GC B细胞中Arid1a缺乏引发的炎症信号招募了中性粒细胞和炎性单核细胞，最终破坏了生发中心的稳态。用抗炎糖皮质激素受体信号减弱炎症信号挽救了缺乏Arid1a的B细胞的GC B细胞分化，从而突出了炎症在阻碍生发中心反应中的关键作用。总之，我们的工作确定了依赖Arid1a的BAF活性在促进有效的生发中心反应中的重要功能。这些发现进一步支持了一种新出现的范式，即如在严重细菌和病毒感染的背景下所报道的，不受控制的炎症会限制GC衍生的体液反应。
