UC San Diego

CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets. Though many of the key transcription factors that govern effector and memory differentiation have been identified, our understanding of how differentiation is transcriptionally and epigenetically regulated is incomplete. In particular how chromatin is site-specifically remodeled during their differentiation is unclear. Given its critical role in regulating chromatin and enhancer accessibility through its nucleosome remodeling activities, we investigated the role of the canonical BAF (cBAF) chromatin remodeling complex in antiviral CD8+ T cells during infection. ARID1A, a subunit of cBAF, was recruited early after activation and established de novo open chromatin regions at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation, gene expression, and failure to undergo terminal effector differentiation. While Arid1a was dispensable for circulating memory cell formation per se, functionality and recall capacity was strongly impaired in the absence of Arid1a. Furthermore, tissue-resident memory formation was strongly impaired in Arid1a-deficient cells. Inducible deletion of Arid1a several days after priming in vivo also led to strongly diminished terminal effector differentiation, indicating that terminal fate determining events require continuous cBAF activity in order for terminal effector cells to form. Arid1b, Pbrm1 (PBAF-specific), and Brd9 (ncBAF-specific) deletions had minimal impact on effector cell differentiation. Thus, ARID1A-containing cBAF governs the enhancer landscape of activated CD8+ T cells that orchestrates TF recruitment and activity and the acquisition of specific effector and memory differentiation states.