Canonical BAF complex activity shapes the enhancer landscape that licenses CD8+ T cell effector and memory fates

Bryan McDonald; Brent Y Chick; Nasiha S Ahmed; Mannix Burns; Shixin Ma; Eduardo Casillas; Dan Chen; Thomas H Mann; Carolyn O'Connor; Nasun Hah; Diana C Hargreaves; Susan M Kaech

doi:10.1016/j.immuni.2023.05.005

Canonical BAF complex activity shapes the enhancer landscape that licenses CD8⁺ T cell effector and memory fates

Immunity. 2023 Jun 13;56(6):1303-1319.e5. doi: 10.1016/j.immuni.2023.05.005.

Authors

Bryan McDonald¹, Brent Y Chick², Nasiha S Ahmed³, Mannix Burns³, Shixin Ma⁴, Eduardo Casillas⁴, Dan Chen⁴, Thomas H Mann⁴, Carolyn O'Connor⁵, Nasun Hah⁶, Diana C Hargreaves⁷, Susan M Kaech⁸

Affiliations

¹ NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Biomedical Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA.
² Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Biological Sciences Graduate Program, University of California at San Diego, La Jolla, CA 92093, USA.
³ Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁴ NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁵ Flow Cytometry Core, The Salk Institute for Biological Studies, La Jolla, CA, USA.
⁶ Chapman Charitable Foundations Genomic Sequencing Core, The Salk Institute for Biological Studies, La Jolla, CA, USA.
⁷ Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: dhargreaves@salk.edu.
⁸ NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: skaech@salk.edu.

PMID: 37315534
PMCID: PMC10281564 (available on 2024-06-13)
DOI: 10.1016/j.immuni.2023.05.005

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.

Keywords: ARID1A; BAF complex; CD8(+) T cells; antiviral immunity; chromatin remodeling; effector T cell; epigenetics; immunotherapy; memory T cell.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents
CD8-Positive T-Lymphocytes*
Chromatin
Nucleosomes
Regulatory Sequences, Nucleic Acid*

Substances

Chromatin
Nucleosomes
Antiviral Agents

Abstract

Publication types

MeSH terms

Substances

Grants and funding