1. Canonical BAF complex activity shapes the enhancer landscape that licenses CD8+ T cell effector and memory fates.
- Author
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McDonald, Bryan, Chick, Brent, Ahmed, Nasiha, Burns, Mannix, Ma, Shixin, Casillas, Eduardo, Chen, Dan, Mann, Thomas, OConnor, Carolyn, Hah, Nasun, Hargreaves, Diana, and Kaech, Susan
- Subjects
ARID1A ,BAF complex ,CD8(+) T cells ,antiviral immunity ,chromatin remodeling ,effector T cell ,epigenetics ,immunotherapy ,memory T cell ,CD8-Positive T-Lymphocytes ,Regulatory Sequences ,Nucleic Acid ,Chromatin ,Nucleosomes ,Antiviral Agents - Abstract
CD8+ T cells provide host protection against pathogens by differentiating into distinct effector and memory cell subsets, but how chromatin is site-specifically remodeled during their differentiation is unclear. Due to 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 (OCRs) at enhancers. Arid1a deficiency impaired the opening of thousands of activation-induced enhancers, leading to loss of TF binding, dysregulated proliferation and gene expression, and failure to undergo terminal effector differentiation. Although Arid1a was dispensable for circulating memory cell formation, tissue-resident memory (Trm) formation was strongly impaired. Thus, 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.
- Published
- 2023