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 2

BRD7 controls SLEC differentiation.

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BRD7 controls SLEC differentiation. (A) Flow cytometry of influenza H-2D...
(A) Flow cytometry of influenza H-2Db-NP+CD8+ and H-2Db-PA+CD8+ T cells from spleen and lungs of BRD7 WT (Brd7fl/fl) (n = 4) and BRD7-deficient (Brd7ΔT) (n = 3) mice. Mice were infected with influenza HKx31 virus, and NP366 and PA244 tetramer were stained in lung or spleen CD8+ T cells at 10 d p.i. (B and C) Frequency and cell number of H-2Db-NP+ or H-2Db-PA+ cells among CD8+ T cells in A. (D and E) Flow cytometry of KLRG1 and CD127 on H-2Db-NP+CD8+ T cells in the lungs obtained from Brd7fl/fl (n = 4) or Brd7ΔT (n = 3) mice infected with HKx31 at 10 d p.i. (F) Flow cytometry of H-2Db-NP+CD8+ T cells from spleen and lungs of PR8-primed Brd7fl/fl (n = 4) and Brd7ΔT (n = 4) mice rechallenged with HKx31 at 6 weeks after PR8 infection. (G) Flow cytometry of KLRG1 and CD127 on H-2Db-NP+CD8+ T cells in the spleen obtained of PR8-primed Brd7fl/fl (n = 4) and Brd7ΔT (n = 4) mice rechallenged with HKx31 at 6 weeks after PR8 infection. (H and I) Flow cytometry of KLRG1 and CD45.1 on NP+CD8+ T cells from chimeras. Mixed bone marrow chimeras were generated by reconstitution of lethally irradiated CD45.1 mice with bone marrow from Brd7fl/fl (CD45.2+) plus Brd7fl/fl (CD45.1+CD45.2+) (n = 3), or Brd7ΔT (CD45.2+) plus Brd7fl/fl (CD45.1+CD45.2+) (n = 3) at a ratio of 1:1. Chimeras were infected with HKx31 at 6 weeks after reconstitution and were sacrificed at 10 d p.i. for analysis. (J–M) Flow cytometry of OT-I CD8+ T cells (J and K) or KLRG1+CD127– SLECs and KLRG1–CD127+ MPECs (L and M) in CD45.1 host mice (n = 4) 9 days after transfer of Brd7fl/fl (CD45.1+CD45.2+) plus Brd7ΔT (CD45.2+) OT-I CD8+ T cells at a ratio of 1:1 and infection with PR8-OVA virus 1 day after transfer. Data are shown as mean ± SEM. **P < 0.01 (2-tailed Student’s t test). Data are representative of 3 independent experiments.