BRD7 as key factor in PBAF complex assembly and CD8+ T cell differentiation
Feng Huang, Yingtong Lin, Yidan Qiao, Yaochang Yuan, Zhihan Zhong, Baohong Luo, Yating Wu, Jun Liu, Jingliang Chen, Wanying Zhang, Hui Zhang, Bingfeng Liu
Feng Huang, Yingtong Lin, Yidan Qiao, Yaochang Yuan, Zhihan Zhong, Baohong Luo, Yating Wu, Jun Liu, Jingliang Chen, Wanying Zhang, Hui Zhang, Bingfeng Liu
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Research Article Immunology Infectious disease

BRD7 as key factor in PBAF complex assembly and CD8+ T cell differentiation

Abstract

Upon infection, naive CD8+ T cells differentiate into cytotoxic effector cells to eliminate the pathogen-infected cells. Although many mechanisms underlying this process have been demonstrated, the regulatory role of chromatin remodeling system in this process remains largely unknown. Here we show that BRD7, a component of the polybromo-associated BAF complex (PBAF), was required for naive CD8+ T cells to differentiate into functional short-lived effector cells (SLECs) in response to acute infections caused by influenza virus or lymphocytic choriomeningitis virus (LCMV). BRD7 deficiency in CD8+ T cells resulted in profound defects in effector population and functions, thereby impairing viral clearance and host recovery. Further mechanical studies indicate that the expression of BRD7 significantly turned to high from naive CD8+ T cells to effector cells, which bridged BRG1 and PBRM1 to the core module of PBAF complex, consequently facilitating the assembly of PBAF complex rather than BAF complex in the effector cells. The PBAF complex changed the chromatin accessibility at the loci of Tbx21 gene and upregulated its expression, leading to the maturation of effector T cells. Our research demonstrates that BRD7 and the PBAF complex are key in CD8+ T cell development and present a significant target for advancing immune therapies.

Authors

Feng Huang, Yingtong Lin, Yidan Qiao, Yaochang Yuan, Zhihan Zhong, Baohong Luo, Yating Wu, Jun Liu, Jingliang Chen, Wanying Zhang, Hui Zhang, Bingfeng Liu

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Figure 5

BRD7 orchestrates the expression of genes critical for SLEC differentiation.

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BRD7 orchestrates the expression of genes critical for SLEC differentiat...
(A) Scatter plot analysis of differentially expressed genes of NP+CD8+ T cells from Brd7fl/fl and Brd7ΔT mice infected with HKx31 at 10 d p.i. FDR ≤ 0.05 and log2 fold change ≥ 2 were used as the threshold to evaluate the significance of differences in gene expression. (B) Gene set enrichment analysis (GSEA) in A among transcriptional differences between naive and activated CD8+ T cells (left) or memory and effector cells (right). NES, normalized enrichment score. (C) Differentially expressed genes of transcription factor (red), chemokine receptors (black), adhesion molecules (blue), and killer cell lectin-like receptors (pink) between WT and BRD7-deficient cells, represented as the log2 fold change. The y axis displays the log2 fold change of each DEG, and the x axis lists the gene name. (D) Genome browser tracks displaying RNA-Seq and ATAC-Seq data at a selected locus comparing WT and BRD7-deficient cells. Tag density from different groups was calculated by normalizing to the total mapped reads. (E) qPCR analysis of mRNA in BRD7-deficient naive CD8+ T cells (TN) or NP+CD8+ T cells (Teff) (n = 4) presented relative to expression in BRD7 WT cells (n = 4). Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 (2-tailed Student’s t test). Data are representative of 2 independent experiments.