Regulation of CTLA-4 expression during T cell activation.
Regulation of CTLA-4 expression during T cell activation.
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DOI：
10.4049/jimmunol.156.11.4154
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发表时间：
1996-06
影响因子：
4.4
通讯作者：
D. L. Perkins;Zemin Wang;Carolyn E. Donovan;H. He;David A. Mark;Guimin Guan;Yunsheng Wang;Yunsheng Wang;T. L. Walunas;J. Bluestone;J. Listman;Patricia W. Finn
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文献类型：
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作者：
D. L. Perkins;Zemin Wang;Carolyn E. Donovan;H. He;David A. Mark;Guimin Guan;Yunsheng Wang;Yunsheng Wang;T. L. Walunas;J. Bluestone;J. Listman;Patricia W. Finn
T细胞激活至少需要两种不同的信号，包括通过ag特异性TCR和共刺激途径发出的信号。最具特征的共刺激途径涉及CD28分子，该分子在T细胞上组成性表达，并结合apc上的B7对抗受体家族。抑制这一共刺激途径可阻止T细胞活化，并可导致T细胞长期无反应或能量不足。相比之下，与CD28同源的CTLA4已被证明是T细胞活化的负调节因子。CTLA4分子不在静止T细胞上表达，而是在T细胞激活的初始步骤后被诱导。为了解决CTLA4表达的调控，我们分析了CTLA4在细胞表面表达、mRNA、转录率和信息衰减率的水平。核径流结果显示在T细胞激活后转录率增加。我们通过Northern blot分析非T细胞，包括B细胞、肥大细胞瘤和成纤维细胞，仅检测到T细胞表达CTLA4。报告基因分析表明，上游CTLA4序列335bp足以控制诱导性。我们已经确定了控制诱导和细胞特异性CTLA4表达的重要调控区域。这些结果也表明，正响应元件和负响应元件都可以调节CTLA4基因表达的转录调控。了解CTLA4的调控有助于在分子水平上深入了解T细胞活化的调控。
T cell activation requires at least two distinct signals, including signaling via the Ag-specific TCR and a costimulatory pathway. The best characterized costimulatory pathway involves the CD28 molecule, which is expressed constitutively on T cells and binds the family of B7 counter-receptors on APCs. Inhibition of this costimulatory pathway prevents T cell activation and can lead to long-term T cell unresponsiveness or anergy. In contrast, CTLA4, which is homologous to CD28, has been shown to be a negative regulator of T cell activation. The CTLA4 molecule is not expressed on resting T cells, but is induced after the initial steps of T cell activation. To address the regulation of CTLA4 expression, we have analyzed CTLA4 at the level of cell surface expression, mRNA, rate of transcription, and rate of decay of message. Nuclear runoff results show an increase in the rate of transcription following T cell activation. Our analyses of non-T cells, including B cells, mastocytoma, and fibroblasts, by Northern blot analysis detect only T cell expression of CTLA4. Reporter gene analysis indicates that 335 bp of upstream CTLA4 sequence are sufficient to control inducibility. We have identified important regulatory regions that control inducible and cell-specific CTLA4 expression. These results also suggest that both positive and negative response elements modulate the transcriptional regulation of CTLA4 gene expression. Understanding the regulation of CTLA4 should provide insight into the regulation of T cell activation at the molecular level.