Regulation of germinal center homeostasis by the BAF complex

Summary/Abstract Germinal Centers (GCs) are specialized anatomical sites in the secondary lymphoid tissues where high-quality adaptive immune responses are mounted. B cells within GCs undergo intricate transcriptional and epigenetic transitions to ultimately generate effective humoral immune responses. During the GC B cell responses, specific transcription factors define distinct stages of cellular differentiation, and efficient chromatin remodeling ensures systematic transition between these transcriptional programs. Brg1/Brm-associated factor (BAF) complexes are highly conserved nucleosomal remodelers that play pivotal roles in establishing cell-specific gene expression programs during cellular differentiation and development. Notably, BAF subunits ARID1A, ARID1B, and SMARCA4, are each mutated in ~10% of Diffuse Large B-Cell Lymphoma (DLBCL) originating from GCs, underscoring the regulatory functions of BAF complex activity in maintaining GC homeostasis. However, the specific contributions of distinct BAF complexes in GC biology remains unclear. Our recent studies showed that the AT-rich interacting domain 1 (Arid1a) dependent canonical BAF complex (Arid1a-cBAF), is indispensable for GC responses, and therefore, generation of high-affinity antibodies. Arid1a- deficient B cells can initiate the GC program but fail to sustain GC responses. We identified important roles of Arid1a-cBAF for establishing permissive chromatin landscapes during B cell differentiation, and simultaneously suppressing inflammatory gene programs to maintain transcriptional fidelity in GCs. Moreover, inflammatory signatures emanating from Arid1a-deficient B cells led to enhanced neutrophil and monocyte recruitment and anti-inflammatory glucocorticoids rescued the differentiation of Arid1a-deficient GCs. These studies suggest that Arid1a-cBAF activity restricts inflammatory signals through both cell-intrinsic and -extrinsic mechanisms to preserve GC responses. We hypothesize that Arid1a-dependent BAF activity establishes the GC transcriptional program and simultaneously restricts inflammatory signatures to promote efficient GC B cell responses. To address this hypothesis in this proposal we will: i) elucidate the epigenetic control of GC B cell differentiation by Arid1a-cBAF activity (Aim1) ii) examine the roles of inflammatory signatures associated with Arid1a loss in disrupting GC responses (Aim2) iii) define altered immunological landscapes and dissect their contributions to perturbation of GCs upon Arid1a loss (Aim3). In summary, the proposed studies will provide comprehensive mechanistic insights for the role of cBAF-mediated nucleosomal remodeling in establishing robust GC responses. These efforts will enhance our broader understanding of inflammation and immunity. In addition, our work will add to an emerging paradigm describing a paradoxical role of unrestrained inflammation in limiting GC responses, commonly seen in patients with severe pathogen infections and sepsis.