Special Key Laboratory of Gene Detection and Therapy of Guizhou Provincial Education Department, Guizhou, China.
Department of Immunology, Zunyi Medical College, Guizhou, China.
Clin Exp Immunol. 2018 Feb;191(2):166-179. doi: 10.1111/cei.13067. Epub 2017 Oct 30.
Recent evidence has shown that microRNA-126 (miR-126) has been involved in the development and function of immune cells, which contributed to the pathogenesis of related clinical diseases. However, the potential role of miR-126 in the development and function of CD4 T cells remains largely unknown. Here we first found that the activation and proliferation, as well as the expression of interferon (IFN)-γ, of CD4 T cells from miR-126 knock-down (KD) mice using the miRNA-sponge technique were enhanced significantly in vitro, compared with those in CD4 T cells from wild-type (WT) mice. To monitor further the possible effect of miR-126 deficiency on the function of CD4 T cells in vivo, we used dextran sulphate sodium (DSS)-induced murine model of acute autoimmune colitis and found that miR-126 deficiency could elevate the pathology of colitis. Importantly, the proportion of CD4 T cells in splenocytes increased significantly in miR-126KD mice. Moreover, the expression levels of CD69 and CD44 on CD4 T cells increased significantly and the expression level of CD62L decreased significantly. Of note, adoptive cell transfer assay showed that the pathology of colitis was more serious in carboxyfluorescein succinimidyl ester (CFSE)-labelled miR-126KD CD4 T cell-transferred group, compared with that in the CFSE-labelled WT CD4 T cells transferred group. Consistently, the expression levels of CD69 and CD44 on CFSE cells increased significantly. Furthermore, both the proliferation and IFN-γ secretion of CFSE cells also increased significantly in the CFSE-labelled miR-126KD CD4 T cell-transferred group. Mechanistic evidence showed that the expression of insulin receptor substrate 1 (IRS-1), as a functional target of miR-126, was elevated in CD4 T cells from miR-126KD mice, accompanied by altered transduction of the extracellular regulated kinase, protein B (AKT) and nuclear factor kappa B (NF-κB) pathway. Our data revealed a novel role in which miR-126 was an intrinsic regulator in the function of CD4 T cells, which provided preliminary basis for exploring further the role of miR-126 in the development, function of CD4 T cells and related clinical diseases.
最近的证据表明，microRNA-126（miR-126）参与了免疫细胞的发育和功能，这有助于相关临床疾病的发病机制。然而，miR-126在 CD4 T 细胞的发育和功能中的潜在作用在很大程度上仍然未知。在这里，我们首次使用 miRNA 海绵技术发现，与野生型（WT）小鼠的 CD4 T 细胞相比，miR-126 敲低（KD）小鼠的 CD4 T 细胞的激活、增殖以及干扰素（IFN）-γ的表达显著增强。为了进一步监测 miR-126 缺乏对 CD4 T 细胞在体内功能的可能影响，我们使用葡聚糖硫酸钠（DSS）诱导的急性自身免疫性结肠炎小鼠模型，发现 miR-126 缺乏可加重结肠炎的病理。重要的是，miR-126KD 小鼠脾细胞中 CD4 T 细胞的比例显著增加。此外，CD4 T 细胞上的 CD69 和 CD44 的表达水平显著增加，CD62L 的表达水平显著降低。值得注意的是，细胞转移实验表明，与 CFSE 标记的 WT CD4 T 细胞转移组相比，CFSE 标记的 miR-126KD CD4 T 细胞转移组的结肠炎病理更严重。一致地，CFSE 细胞上的 CD69 和 CD44 的表达水平显著增加。此外，CFSE 标记的 miR-126KD CD4 T 细胞转移组中的 CFSE 细胞的增殖和 IFN-γ 分泌也显著增加。机制证据表明，作为 miR-126 的功能靶标胰岛素受体底物 1（IRS-1）的表达在 miR-126KD 小鼠的 CD4 T 细胞中升高，伴随着细胞外调节激酶、蛋白 B（AKT）和核因子 kappa B（NF-κB）途径的转导改变。我们的数据揭示了 miR-126 作为 CD4 T 细胞功能的内在调节剂的新作用，为进一步探索 miR-126 在 CD4 T 细胞的发育、功能及相关临床疾病中的作用提供了初步依据。
