Negative transcriptional regulation in anergic T cells.
Negative transcriptional regulation in anergic T cells.
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无反应性 T 细胞中的负转录调控。
DOI：
10.1073/pnas.92.6.2375
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发表时间：
1995
影响因子：
11.1
通讯作者：
Reisfeld,RA
中科院分区：
文献类型：
--
作者：
Becker,JC;Brabletz,T;Kirchner,T;Conrad,CT;Bröcker,EB;Reisfeld,RA
无反应性是在不存在共刺激的情况下由抗原受体刺激诱导的T淋巴细胞耐受的机制，由此T细胞在抗原诱导的白细胞介素2（IL-2）基因转录中表现出缺陷。在这里，我们提出的证据，在无能的T细胞负IL-2基因调控的机制。在诱导无反应性后不久，在人T细胞的核提取物中检测到与IL-2启动子的负调控元件A（NRE-A）的大量结合活性。这种核复合物的快速诱导被环孢菌素A阻断，并且被发现与蛋白质合成无关。将含有人佛波醇12-肉豆蔻酸酯13-乙酸酯响应元件（PRE）或NRE-A和PRE两者的质粒DNA用作在T细胞核提取物存在下进行体外转录测定的模板。在这些条件下，来自无反应性和静息T细胞克隆的核提取物在CD 3和CD 28交联后，诱导仅含有PRE的质粒的转录。然而，当使用含有NRE-A和PRE的质粒时，转录仅由来自静息T细胞而不是无反应性T细胞的核提取物诱导。这些发现表明在无能T细胞中IL-2基因的转录抑制的功能相关性。
Anergy is a mechanism of T-lymphocyte tolerance induced by antigen-receptor stimulation in the absence of costimulation, whereby T cells exhibit a defect in antigen-induced transcription of the interleukin 2 (IL-2) gene. Here we present evidence for a mechanism of negative IL-2 gene regulation in anergic T cells. High amounts of binding activity to the negative regulatory element A (NRE-A) of the IL-2 promotor were detected in nuclear extracts from human T cells shortly after induction of anergy. Rapid induction of this nuclear complex is blocked by cyclosporin A and is found to be independent of protein synthesis. Plasmid DNAs, containing either the human phorbol 12-myristate 13-acetate-responsive element (PRE) or both NRE-A and PRE, were used as template for in vitro transcription assays in the presence of T-cell nuclear extracts. Under these conditions nuclear extracts from both anergic and rested T-cell clones, after crosslinking of CD3 and CD28, induced transcription of plasmids containing only PRE. However, when plasmids containing NRE-A and PRE were used, transcription was only induced by nuclear extracts from rested but not anergic T cells. These findings suggest the functional relevance of transcriptional repression of the IL-2 gene in anergic T cells.