Regulation of AP-1 and NFAT transcription factors during thymic selection of T cells
Regulation of AP-1 and NFAT transcription factors during thymic selection of T cells
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DOI：
10.1128/mcb.16.3.1074
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发表时间：
1996-03
影响因子：
5.3
通讯作者：
Mercedes Rincón;R. A. Flavell
中科院分区：
文献类型：
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作者：
Mercedes Rincón;R. A. Flavell
胸腺细胞表达细胞因子基因的能力在胸腺发育的不同阶段发生变化。尽管CD 4-CD 8-胸腺细胞能够响应于T细胞受体（TcR）非依赖性刺激而产生广谱细胞因子，但当它们接近双阳性（DP）CD 4 + CD 8+阶段时，它们失去产生细胞因子的能力。在DP阶段之后，胸腺细胞变成单阳性的CD 4+或CD 8+胸腺细胞，其重新获得分泌细胞因子的能力。为了了解这种特异性调控的分子基础，我们使用AP-1-荧光素酶和新产生的NFAT-荧光素酶转基因小鼠来分析这两种参与细胞因子基因表达调控的转录因子的转录和DNA结合活性。在这里，我们表明，AP-1和NFAT的转录活性是不能诱导的DP细胞中的大多数，但在DP细胞分化到成熟的单阳性阶段，胸腺细胞恢复这种诱导。亚群分析表明，这种诱导是重新获得在DP阶段前下调的共受体之一。事实上，AP-1诱导，就像表达白细胞介素-2基因的能力一样，在DP TcR低CD 69低热稳定抗原（HSA）高胸腺细胞分化为DP TcR高CD 69高HSA高细胞期间重新获得，这被认为是启动阳性选择的第一个信号的结果。因此，我们提出，DP胸腺细胞不能诱导AP-1和NFAT的活动是缺乏细胞因子基因表达在这个阶段的原因之一，这种诱导在DP分化的最后阶段作为一个积极的选择的结果重新获得。这可能是一种机制，以防止DP胸腺细胞的激活之前，选择已经发生。
The ability of thymocytes to express cytokine genes changes during the different stages of thymic development. Although CD4- CD8- thymocytes are able to produce a wide spectrum of cytokines in response to a T-cell receptor (TcR)-independent stimulus, as they approach the double-positive (DP) CD4+ CD8+ stage, they lose the ability to produce cytokine. After the DP stage, thymocytes become single-positive CD4+ or CD8+ thymocytes which reacquire the ability to secrete cytokines. In an attempt to understand the molecular basis of this specific regulatin, we use AP-1-luciferase and newly generated NFAT-luciferase transgenic mice to analyze the transcriptional and DNA-binding activities of these two transcription factors that are involved in the regulation of cytokine gene expression. Here, we show that both AP-1 and NFAT transcriptional activities are not inducible in the majority of DP cells but that during the differentiation of DP cells to the mature single-positive stage, thymocytes regain this inducibility. Subpopulation analysis demonstrates that this inducibility is reacquired at the DP stage before the down-modulation of one of the coreceptors. Indeed AP-1 inducibility, just like the ability to express the interleukin-2 gene, is reacquired during the differentiation of DP TcRlow CD69low heat-stable antigen (HSA)high thymocytes to DP TcRhigh CD69high HSAhigh cells, which is considered to be the consequence of the first signal that initiates positive selection. We therefore propose that the inability of DP thymocytes to induce AP-1 and NFAT activities is one of the causes for the lack of cytokine gene expression at this stage and that this inducibility is reacquired at the latest stage of DP differentiation as a consequence of positive selection. This could be a mechanism to prevent the activation of DP thymocytes before selection has taken place.