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Notch ligand Delta-like 4 induces epigenetic regulation of Treg cell differentiation and function in viral infection.
Mucosal Immunology ( IF 7.9 ) Pub Date : 2018-09-01 , DOI: 10.1038/s41385-018-0052-1
Hung-An Ting 1, 2 , Denise de Almeida Nagata 1, 3 , Andrew J Rasky 1 , Carrie-Anne Malinczak 1, 2 , Ivan P Maillard 4, 5, 6 , Matthew A Schaller 1 , Nicholas W Lukacs 1, 2
Affiliation  

Notch ligand Delta-like ligand 4 (DLL4) has been shown to regulate CD4 T-cell differentiation, including regulatory T cells (Treg). Epigenetic alterations, which include histone modifications, are critical in cell differentiation decisions. Recent genome-wide studies demonstrated that Treg have increased trimethylation on histone H3 at lysine 4 (H3K4me3) around the Treg master transcription factor, Foxp3 loci. Here we report that DLL4 dynamically increased H3K4 methylation around the Foxp3 locus that was dependent upon upregulated SET and MYDN domain containing protein 3 (SMYD3). DLL4 promoted Smyd3 through the canonical Notch pathway in iTreg differentiation. DLL4 inhibition during pulmonary respiratory syncytial virus (RSV) infection decreased Smyd3 expression and Foxp3 expression in Treg leading to increased Il17a. On the other hand, DLL4 supported Il10 expression in vitro and in vivo, which was also partially dependent upon SMYD3. Using genome-wide unbiased mRNA sequencing, novel sets of DLL4- and Smyd3-dependent differentially expressed genes were discovered, including lymphocyte-activation gene 3 (Lag3), a checkpoint inhibitor that has been identified for modulating Th cell activation. Together, our data demonstrate a novel mechanism of DLL4/Notch-induced Smyd3 epigenetic pathways that maintain regulatory CD4 T cells in viral infections.

中文翻译:

Notch 配体 Delta-like 4 在病毒感染中诱导 Treg 细胞分化和功能的表观遗传调节。

Notch 配体 Delta 样配体 4 (DLL4) 已显示可调节 CD4 T 细胞分化,包括调节性 T 细胞 (T reg )。表观遗传改变,包括组蛋白修饰,在细胞分化决定中至关重要。最近的全基因组研究表明,T reg在 T reg主转录因子 Foxp3 基因座周围的赖氨酸 4 (H3K4me3) 上增加了组蛋白 H3 的三甲基化。在这里,我们报告 DLL4 动态增加 Foxp3 基因座周围的 H3K4 甲基化,这取决于上调的 SET 和 MYDN 结构域含有蛋白 3 (SMYD3)。DLL4 通过 iT reg中的规范 Notch 通路促进 Smyd3分化。肺呼吸道合胞病毒 (RSV) 感染期间的 DLL4 抑制降低了 T reg中的 Smyd3 表达和 Foxp3 表达,导致 Il17a 增加。另一方面,DLL4 支持 Il10 在体外和体内的表达,这也部分依赖于 SMYD3。使用全基因组无偏 mRNA 测序,发现了一组新的 DLL4 和 Smyd3 依赖性差异表达基因,包括淋巴细胞激活基因 3 (Lag3),这是一种已被确定用于调节 Th 细胞激活的检查点抑制剂。总之,我们的数据证明了 DLL4/Notch 诱导的 Smyd3 表观遗传途径的一种新机制,该途径在病毒感染中维持调节性 CD4 T 细胞。
更新日期:2018-07-24
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