Severin Mary E, Lee Priscilla W, Liu Yue, Selhorst Amanda J, Gormley Matthew G, Pei Wei, Yang Yuhong, Guerau-de-Arellano Mireia, Racke Michael K, Lovett-Racke Amy E
Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, USA Biomedical Sciences Graduate Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, OH, USA Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH, USA.
Brain. 2016 Jun;139(Pt 6):1747-61. doi: 10.1093/brain/aww084. Epub 2016 Apr 28.
Transforming growth factor beta (TGFβ) signalling is critical for regulatory T cell development and function, and regulatory T cell dysregulation is a common observation in autoimmune diseases, including multiple sclerosis. In a comprehensive miRNA profiling study of patients with multiple sclerosis naïve CD4 T cells, 19 differentially expressed miRNAs predicted to target the TGFβ signalling pathway were identified, leading to the hypothesis that miRNAs may be responsible for the regulatory T cell defect observed in patients with multiple sclerosis. Patients with multiple sclerosis had reduced levels of TGFβ signalling components in their naïve CD4 T cells. The differentially expressed miRNAs negatively regulated the TGFβ pathway, resulting in a reduced capacity of naïve CD4 T cells to differentiate into regulatory T cells. Interestingly, the limited number of regulatory T cells, that did develop when these TGFβ-targeting miRNAs were overexpressed, were capable of suppressing effector T cells. As it has previously been demonstrated that compromising TGFβ signalling results in a reduced regulatory T cell repertoire insufficient to control autoimmunity, and patients with multiple sclerosis have a reduced regulatory T cell repertoire, these data indicate that the elevated expression of multiple TGFβ-targeting miRNAs in naïve CD4 T cells of patients with multiple sclerosis impairs TGFβ signalling, and dampens regulatory T cell development, thereby enhancing susceptibility to developing multiple sclerosis.
转化生长因子β（TGFβ）信号传导对于调节性T细胞的发育和功能至关重要，而调节性T细胞功能失调在包括多发性硬化症在内的自身免疫性疾病中很常见。在一项对多发性硬化症初治CD4 T细胞患者的全面miRNA谱分析研究中，鉴定出19种预测靶向TGFβ信号通路的差异表达miRNA，从而提出了miRNA可能是多发性硬化症患者中观察到的调节性T细胞缺陷的原因这一假设。多发性硬化症患者的初治CD4 T细胞中TGFβ信号传导成分水平降低。差异表达的miRNA对TGFβ通路起负调节作用，导致初治CD4 T细胞分化为调节性T细胞的能力降低。有趣的是，当这些靶向TGFβ的miRNA过表达时，有限数量的调节性T细胞确实发育出来，并且能够抑制效应T细胞。由于先前已证明损害TGFβ信号传导会导致调节性T细胞库减少，不足以控制自身免疫，而多发性硬化症患者的调节性T细胞库减少，这些数据表明多发性硬化症患者初治CD4 T细胞中多种靶向TGFβ的miRNA表达升高会损害TGFβ信号传导，并抑制调节性T细胞发育，从而增加患多发性硬化症的易感性。
