NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies, La Jolla, CA, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
Molecular and Cellular Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
Immunity. 2020 Jul 14;53(1):143-157.e8. doi: 10.1016/j.immuni.2020.06.011. Epub 2020 Jul 7.
Regulatory T (Treg) cells play a pivotal role in suppressing auto-reactive T cells and maintaining immune homeostasis. Treg cell development and function are dependent on the transcription factor Foxp3. Here, we performed a genome-wide CRISPR loss-of-function screen to identify Foxp3 regulators in mouse primary Treg cells. Foxp3 regulators were enriched in genes encoding subunits of the SWI/SNF nucleosome-remodeling and SAGA chromatin-modifying complexes. Among the three SWI/SNF-related complexes, the Brd9-containing non-canonical (nc) BAF complex promoted Foxp3 expression, whereas the PBAF complex was repressive. Chemical-induced degradation of Brd9 led to reduced Foxp3 expression and reduced Treg cell function in vitro. Brd9 ablation compromised Treg cell function in inflammatory disease and tumor immunity in vivo. Furthermore, Brd9 promoted Foxp3 binding and expression of a subset of Foxp3 target genes. Our findings provide an unbiased analysis of the genetic networks regulating Foxp3 and reveal ncBAF as a target for therapeutic manipulation of Treg cell function.
调节性 T（Treg）细胞在抑制自身反应性 T 细胞和维持免疫稳态方面发挥着关键作用。Treg 细胞的发育和功能依赖于转录因子 Foxp3。在这里，我们进行了全基因组 CRISPR 功能丧失筛选，以鉴定小鼠原代 Treg 细胞中的 Foxp3 调节因子。Foxp3 调节因子在编码 SWI/SNF 核小体重塑和 SAGA 染色质修饰复合物亚基的基因中富集。在三个 SWI/SNF 相关复合物中，含有 Brd9 的非典型（nc）BAF 复合物促进 Foxp3 的表达，而 PBAF 复合物具有抑制作用。化学诱导的 Brd9 降解导致 Foxp3 表达减少和体外 Treg 细胞功能降低。Brd9 缺失会损害体内炎症性疾病和肿瘤免疫中的 Treg 细胞功能。此外，Brd9 促进了 Foxp3 结合和一组 Foxp3 靶基因的表达。我们的研究结果提供了对调节 Foxp3 的遗传网络的无偏分析，并揭示了 ncBAF 作为 Treg 细胞功能治疗干预的靶点。
