Wells Alexandria C, Daniels Keith A, Angelou Constance C, Fagerberg Eric, Burnside Amy S, Markstein Michele, Alfandari Dominique, Welsh Raymond M, Pobezinskaya Elena L, Pobezinsky Leonid A
Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, United States.
Department of Pathology, University of Massachusetts Medical School, Worcester, United States.
Elife. 2017 Jul 24;6:e26398. doi: 10.7554/eLife.26398.
The differentiation of naive CD8 T cells into effector cytotoxic T lymphocytes upon antigen stimulation is necessary for successful antiviral, and antitumor immune responses. Here, using a mouse model, we describe a dual role for the let-7 microRNAs in the regulation of CD8 T cell responses, where maintenance of the naive phenotype in CD8 T cells requires high levels of let-7 expression, while generation of cytotoxic T lymphocytes depends upon T cell receptor-mediated let-7 downregulation. Decrease of let-7 expression in activated T cells enhances clonal expansion and the acquisition of effector function through derepression of the let-7 targets, including Myc and Eomesodermin. Ultimately, we have identified a novel let-7-mediated mechanism, which acts as a molecular brake controlling the magnitude of CD8 T cell responses.
幼稚CD8 T细胞在抗原刺激下分化为效应细胞毒性T淋巴细胞对于成功的抗病毒和抗肿瘤免疫反应是必要的。在此，我们使用小鼠模型描述了let-7微小RNA在调节CD8 T细胞反应中的双重作用，其中CD8 T细胞中幼稚表型的维持需要高水平的let-7表达，而细胞毒性T淋巴细胞的产生则依赖于T细胞受体介导的let-7下调。活化T细胞中let-7表达的降低通过解除对包括Myc和Eomesodermin在内的let-7靶标的抑制来增强克隆扩增和效应功能的获得。最终，我们确定了一种新的let-7介导的机制，它作为一种分子制动器控制CD8 T细胞反应的强度。
