Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient GC B cell responses [CUT&TAG]

Differentiating B cells in germinal centers (GC) require tightly coordinated transcriptional and epigenetic transitions to generate efficient humoral immune responses. The mammalian BAF (Brg1/Brm-associated factor) 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 the generation of functional humoral immune responses are not well-understood. Here, we show that the Arid1a-dependent canonical BAF (cBAF) complex is indispensable for generatingon of fully mature GCs and high affinity humoral immune responses. While Arid1a-deficient B cells undergo activation to initiate GC responses, they fail to sustain the GC program, resulting incausing premature GC collapse. Mechanistically, Arid1a-dependent cBAF activity establishes permissive chromatin landscapes at several thousand genomic regions during B cell activation and isare 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 recruits neutrophils and inflammatory monocytes, and eventually disrupts GC homeostasis. Remarkably, dampening of inflammatory cues with anti-inflammatory glucocorticoid receptor signaling rescues 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 recent paradigms uncovering a deterministic role of unrestrained inflammation in obstructing GC responses, common in patients with severe bacterial and viral infections. To investigate Arid1a binding (CUT and Tag) in WT and Arid1a KO in B cells, using Cg1cre