Dysregulated miR34a/diacylglycerol kinase ζ interaction enhances T-cell activation in acquired aplastic anemia.
Dysregulated miR34a/diacylglycerol kinase ζ interaction enhances T-cell activation in acquired aplastic anemia.
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失调的 miR34a/二酰甘油激酶 γ 相互作用增强获得性再生障碍性贫血中的 T 细胞活化
DOI：
10.18632/oncotarget.14046
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发表时间：
2017-01-24
期刊：
影响因子：
--
通讯作者：
Peng J
中科院分区：
文献类型：
--
作者：
Sun YX;Li H;Feng Q;Li X;Yu YY;Zhou LW;Gao Y;Li GS;Ren J;Ma CH;Gao CJ;Peng J
获得性再生障碍性贫血是人类骨髓衰竭综合征的特发性范例，其涉及骨髓中细胞毒性T细胞对造血干细胞和祖细胞的主动破坏。T细胞中microRNA的异常表达已被证明会导致某些自身免疫性疾病的发展。在本研究中，我们对再生障碍性贫血患者和健康对照者骨髓CD 3 + T细胞中的miRNA表达进行了微阵列分析。在41例患者中证实了骨髓单个核细胞中miR 34 a的过表达及其靶基因二酰甘油激酶（DGK）的低表达，并与再生障碍性贫血的严重程度相关。此外，miR 34 a的水平在来自患者的初始T细胞中高于来自对照的初始T细胞。在使用miR 34 a −/−小鼠的免疫介导的骨髓衰竭小鼠模型中研究了miR 34 a和DGK β在再生障碍性贫血中的作用。在体外T细胞受体刺激后，与野生型C57 BL 6对照小鼠相比，miR 34 a −/−小鼠的淋巴结T细胞表现出活化和增殖减少，伴随着DGK β表达的不太深刻的下调和ERK磷酸化减少。与注射相同数量的野生型淋巴结细胞相比，将5 × 106 miR 34 a −/−淋巴结T细胞输注到亚致死剂量照射的CB 6 F1受体中导致Lin-Sca 1 + CD 117+细胞增加，CD 8 + T细胞扩增不那么剧烈。我们的研究表明，miR 34 a/DGK调节异常增强再生障碍性贫血中的T细胞活化，靶向miR 34 a可能代表再生障碍性贫血患者的新分子治疗方法。
Acquired aplastic anemia is an idiopathic paradigm of human bone marrow failure syndrome, which involves active destruction of hematopoietic stem cells and progenitors by cytotoxic T cells in the bone marrow. Aberrant expression of microRNAs in T cells has been shown to lead to development of certain autoimmune diseases. In the present study, we performed a microarray analysis of miRNA expression in bone marrow CD3+ T cells from patients with aplastic anemia and healthy controls. Overexpression of miR34a and underexpression of its target gene diacylglycerol kinase (DGK) ζ in bone marrow mononuclear cells were validated in 41 patients and associated with the severity of aplastic anemia. Further, the level of miR34a was higher in naïve T cells from patients than from controls. The role of miR34a and DGKζ in aplastic anemia was investigated in a murine model of immune-mediated bone marrow failure using miR34a−/− mice. After T-cell receptor stimulation in vitro, lymph node T cells from miR34a−/− mice demonstrated reduced activation and proliferation accompanied with a less profound down-regulation of DGKζ expression and decreased ERK phosphorylation compared to those from wild-type C57BL6 control mice. Infusion of 5 × 106 miR34a−/− lymph node T cells into sublethally irradiated CB6F1 recipients led to increased Lin-Sca1+CD117+ cells and less vigorous expansion of CD8+ T cells than injection of same number of wild-type lymph node cells. Our study demonstrates that the miR34a/DGKζ dysregulation enhances T-cell activation in aplastic anemia and targeting miR34a may represent a novel molecular therapeutic approach for patients with aplastic anemia.