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Molecular mechanisms of NF-κB mediated T-cell acitivation induced by HTLV-I Tax

HTLV-I Tax 诱导 NF-κB 介导 T 细胞活化的分子机制

基本信息

批准号：
11670288
负责人：
OHTANI Kiyoshi
金额：
$ 2.3万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670288/
关键词：
gp34 NF-κB HTLV-I Tax T-cell TPA 細胞周期

项目摘要

We examined the role of NF-κB in T-cell activation induced by the oncogene product Tax of human T-cell leukemia virus type I (HTLV-I).gp34 is a cell surface molecule which is expressed on antigen stimulated T-cells and HTLV-I infected T-cells, but not on mitogen stimulated T-cells. Consistent with this, NF-κB like sequence in gp34 promoter is activated by HTLV-I Tax, however it is not activated by TPA treatment unlike typical NF-κB which is activated by TPA treatment. For full understanding of molecular mechanism of T-cell activation by HTLV-I Tax, we have attempted to search for stimulation required for the activation of the NF-κB like sequence in addition to TPA treatment. We transfected gp34 promoter-driven luciferase plasmids into a human T-cell line Jurkat and examined whether the addition of ionomycin or antibodies against cell surface molecules (CD2, CD3, CD4, CD26 and CD28) enhanced reporter activity as compared to TPA treatment alone. Addition of ionomycin and anti-CD28 antibodies enhanced the reporter activity by 8 and 9 folds, respectively, indicating that the signaling pathways originated from increase in Ca concentration and CD28 can activate the gp34 NF-κB like sequence. However, the activation was lower than that by Tax (40 folds), indicating the possibility that Tax activates other pathways than these two.In addition, we showed that Tax can induce cell cycle progression in resting human T-cells using a Tax-expessing recombinant adenovirus and an IL-2 dependent human T-cell line Kit 225. The ability of Tax mutants to induce cell cycle progression paralleled those to activate the NF-κB transcription pathway, indicating that the NF-κB pathway is important for Tax-mediated cell cycle progression. However, overexpression of NF-κB did not induce cell cycle progression. These results indicate that Tax can activate other pathway (s) than typical NF-κB.

我们研究了NF-κB在人T细胞白血病病毒I型（HTLV-I）的癌基因产物Tax诱导的T细胞活化中的作用。gp 34是一种细胞表面分子，在抗原刺激的T细胞和HTLV-I感染的T细胞上表达，但在促分裂原刺激的T细胞上不表达。与此一致，gp 34启动子中的NF-κB样序列被HTLV-1 Tax激活，然而，与典型的NF-κB被TPA处理激活不同，它不被TPA处理激活。为了充分理解HTLV-I Tax激活T细胞的分子机制，我们试图寻找除了TPA处理之外激活NF-κB样序列所需的刺激。我们将gp 34启动子驱动的荧光素酶质粒转染到人T细胞系Jurkat中，并检查与单独TPA处理相比，加入离子霉素或针对细胞表面分子（CD 2、CD 3、CD 4、CD 26和CD 28）的抗体是否增强了报告活性。加入离子霉素和抗CD 28抗体可使报告基因活性分别提高8倍和9倍，表明信号通路来源于Ca浓度的增加，CD 28可激活gp 34 NF-κB样序列。然而，激活低于税收（40倍），表明税收激活其他途径比这两个的可能性。此外，我们表明，税收可以诱导细胞周期的进展，在休息的人T细胞使用Tax表达的重组腺病毒和IL-2依赖的人T细胞系Kit 225。Tax突变体诱导细胞周期进程的能力高于激活NF-κB转录途径的能力，表明NF-κB途径在Tax介导的细胞周期进程中是重要的。然而，NF-κB的过表达并不诱导细胞周期进展。这些结果表明Tax可以激活除典型NF-κB以外的其它途径。