Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells
Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells
复制标题
NuRD 复合物的染色质重塑调节滤泡辅助细胞和调节性 T 细胞的发育
DOI：
10.1073/pnas.1805239115
复制
发表时间：
2018-06-26
影响因子：
11.1
通讯作者：
Leavenworth, Jianmei W.
中科院分区：
文献类型：
--
作者：
Shen, Erxia;Wang, Qin;Leavenworth, Jianmei W.
感染或接种疫苗后产生高亲和力抗体应答需要滤泡辅助性T细胞和滤泡调节性T细胞对生发中心B细胞的精确控制。虽然Bcl 6转录因子在滤泡T细胞分化中起着核心作用，但Bcl 6控制的分子基础仍不确定。在这里，我们报告Bcl 6依赖性控制反映了Bcl 6和Mi-2β-核小体重塑脱乙酰酶复合物（Mi-2β-NuRD）之间形成的大分子复合物。这种核内复合物的抑制活性增强滤泡T细胞表型并抑制替代T细胞命运。这种细胞内复合物的鉴定可能有助于治疗自身免疫性疾病的新的靶向方法。谱系定型和分化为CD 4 + T细胞亚群反映了染色质调节因子和转录因子（TF）之间的相互作用。滤泡T细胞发育受Bcl 6 TF调节，其有助于确定CD 4+滤泡辅助T细胞（TFH）和滤泡调节性T细胞（TFR）的表型和滤泡定位。在这里，我们表明，Bcl 6依赖性控制滤泡T细胞是由Bcl 6和Mi-2β-核小体重塑脱乙酰酶复合物（Mi-2β-NuRD）之间形成的复合物介导的。该复合物的形成反映了骨桥蛋白（OPN-i）的细胞内同种型的贡献，其充当支架以稳定Bcl 6和NuRD复合物之间的结合，Bcl 6和NuRD复合物一起调节TFH和TFR细胞的遗传程序。Bcl 6-NuRD复合物的装配缺陷会扭曲滤泡T细胞分化，导致TFR发育受损，并使TFH谱系向包括Blimp 1、Tbet、颗粒酶B和IFNγ表达的TH 1样程序倾斜。这些发现定义了一个核心Bcl 6-指导的转录复合物，使CD 4+滤泡T细胞调节生发中心的反应。
Significance Production of high-affinity antibody responses after infection or vaccination requires precise control of germinal center B cells by follicular helper T cells and follicular regulatory T cells. Although the Bcl6 transcription factor plays a central role in follicular T cell differentiation, the molecular basis of Bcl6 control has been clouded in uncertainty. Here we report that Bcl6-dependent control reflects the formation of a macromolecular complex between Bcl6 and the Mi-2β-nucleosome remodeling deacetylase complex (Mi-2β-NuRD). The repressive activity of this intranuclear complex potentiates the follicular T cell phenotype and inhibits alternative T cell fates. Identification of this intracellular complex may facilitate new targeted approaches to the treatment of autoimmune disorders. Lineage commitment and differentiation into CD4+ T cell subsets reflect an interplay between chromatin regulators and transcription factors (TF). Follicular T cell development is regulated by the Bcl6 TF, which helps determine the phenotype and follicular localization of both CD4+ follicular helper T cells (TFH) and follicular regulatory T cells (TFR). Here we show that Bcl6-dependent control of follicular T cells is mediated by a complex formed between Bcl6 and the Mi-2β-nucleosome-remodeling deacetylase complex (Mi-2β-NuRD). Formation of this complex reflects the contribution of the intracellular isoform of osteopontin (OPN-i), which acts as a scaffold to stabilize binding between Bcl6 and the NuRD complex that together regulate the genetic program of both TFH and TFR cells. Defective assembly of the Bcl6–NuRD complex distorts follicular T cell differentiation, resulting in impaired TFR development and skewing of the TFH lineage toward a TH1-like program that includes expression of Blimp1, Tbet, granzyme B, and IFNγ. These findings define a core Bcl6-directed transcriptional complex that enables CD4+ follicular T cells to regulate the germinal center response.