Regelin Malte, Blume Jonas, Pommerencke Jens, Vakilzadeh Ramin, Witzlau Katrin, Łyszkiewicz Marcin, Ziętara Natalia, Saran Namita, Schambach Axel, Krueger Andreas
Institute of Immunology, Hannover Medical School, 30625 Hannover, Germany;
Institute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; and Division of Hematology and Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
J Immunol. 2015 Nov 15;195(10):4832-40. doi: 10.4049/jimmunol.1402248. Epub 2015 Oct 16.
miRNAs regulate a large variety of developmental processes including development of the immune system. T cell development is tightly controlled through the interplay of transcriptional programs and cytokine-mediated signals. However, the role of individual miRNAs in this process remains largely elusive. In this study, we demonstrated that hematopoietic cell-specific loss of miR-17∼92, a cluster of six miRNAs implicated in B and T lineage leukemogenesis, resulted in profound defects in T cell development both at the level of prethymic T cell progenitors as well as intrathymically. We identified reduced surface expression of IL-7R and concomitant limited responsiveness to IL-7 signals as a common mechanism resulting in reduced cell survival of common lymphoid progenitors and thymocytes at the double-negative to double-positive transition. In conclusion, we identified miR-17∼92 as a critical modulator of multiple stages of T cell development.
微小RNA（miRNA）调控多种发育过程，包括免疫系统的发育。T细胞发育通过转录程序和细胞因子介导的信号之间的相互作用受到严格控制。然而，单个miRNA在此过程中的作用仍 largely难以捉摸。在本研究中，我们证明了miR-17∼92（一组与B和T谱系白血病发生有关的六个miRNA）在造血细胞中的特异性缺失，导致胸腺前T细胞祖细胞水平以及胸腺内T细胞发育出现严重缺陷。我们发现白细胞介素-7受体（IL-7R）的表面表达降低以及对IL-7信号的反应性有限是导致普通淋巴祖细胞和胸腺细胞在双阴性到双阳性转变时细胞存活率降低的共同机制。总之，我们确定miR-17∼92是T细胞发育多个阶段的关键调节因子。
