Department of Immunology, School of Medicine, Yangzhou University, Yangzhou 225000, PR China; Vaccine and Immunotherapy Center, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Department of Immunology, School of Medicine, Yangzhou University, Yangzhou 225000, PR China.
Cell Signal. 2020 Dec;76:109800. doi: 10.1016/j.cellsig.2020.109800. Epub 2020 Oct 1.
NK1.1 CD4 NKG2D T cells are a subpopulation of regulatory T cells that downregulate the functions of CD4 T, CD8 T, natural killer (NK) cells, and macrophages through TGF-β1 production. Early growth response genes 2 (Egr2) and 3 (Egr3) maintain immune homeostasis by modulating T lymphocyte development, inhibiting effector T cell function, and promoting the induction of regulatory T cells. Whether Egr2 and Egr3 directly regulate TGF-β1 transcription in NK1.1 CD4 NKG2D T cells remains elusive. The expression levels of Egr2 and Egr3 were higher in NK1.1 CD4 NKG2D T cells than in NK1.1 CD4 NKG2D T cells. Egr2 and Egr3 expression were remarkably increased after stimulating NK1.1 CD4 NKG2D T cells with sRAE or α-CD3/sRAE. The ectopic expression of Egr2 or Egr3 resulted in the enhancement of TGF-β1 expression, while knockdown of Egr2 or Egr3 led to the decreased expression of TGF-β1 in NK1.1 CD4 NKG2D T cells. Egr2 and Egr3 directly bound with the TGF-β1 promoter as demonstrated by the electrophoretic mobility shift assay and dual-luciferase gene reporter assay. Furthermore, the Egr2 and Egr3 expression of NK1.1 CD4 NKG2D T cells could be induced by the AP-1 and NF-κB transcriptional factors, but had no involvement with the activation of NF-AT and STAT3. In conclusion, Egr2 and Egr3 induced by AP-1 and NF-κB directly initiate TGF-β1 transcription in NK1.1 CD4 NKG2D T cells. This study indicates that manipulating Egr2 and Egr3 expression would potentiate or alleviate the regulatory function of NK1.1 CD4 NKG2D T cells and this strategy could be used in the therapy for patients with autoimmune diseases or tumor.
自然杀伤细胞 1.1（NK1.1）+CD4+NKG2D+T 细胞是调节性 T 细胞的一个亚群，通过 TGF-β1 的产生来下调 CD4+T、CD8+T、自然杀伤（NK）细胞和巨噬细胞的功能。早期生长反应基因 2（Egr2）和 3（Egr3）通过调节 T 淋巴细胞的发育、抑制效应 T 细胞的功能和促进调节性 T 细胞的诱导来维持免疫稳态。Egr2 和 Egr3 是否直接调节 NK1.1+CD4+NKG2D+T 细胞中的 TGF-β1 转录仍不清楚。NK1.1+CD4+NKG2D+T 细胞中的 Egr2 和 Egr3 表达水平高于 NK1.1+CD4+NKG2D-T 细胞。用 sRAE 或 α-CD3/sRAE 刺激 NK1.1+CD4+NKG2D+T 细胞后，Egr2 和 Egr3 的表达显著增加。Egr2 或 Egr3 的异位表达导致 TGF-β1 表达增强，而 Egr2 或 Egr3 的敲低导致 NK1.1+CD4+NKG2D+T 细胞中 TGF-β1 表达降低。电泳迁移率变动分析和双荧光素酶基因报告基因分析表明，Egr2 和 Egr3 直接与 TGF-β1 启动子结合。此外，NK1.1+CD4+NKG2D+T 细胞中的 Egr2 和 Egr3 表达可被 AP-1 和 NF-κB 转录因子诱导，但与 NF-AT 和 STAT3 的激活无关。总之，AP-1 和 NF-κB 诱导的 Egr2 和 Egr3 直接启动 NK1.1+CD4+NKG2D+T 细胞中的 TGF-β1 转录。本研究表明，操纵 Egr2 和 Egr3 的表达可以增强或减轻 NK1.1+CD4+NKG2D+T 细胞的调节功能，该策略可用于治疗自身免疫性疾病或肿瘤患者。
