Peng Siying, Lalani Saif, Leavenworth Jianmei W, Ho I-Cheng, Pauza Mary E
Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794, USA.
Eur J Immunol. 2007 Oct;37(10):2868-80. doi: 10.1002/eji.200636979.
The transcription factor c-Maf is critical for IL-4 production and the development of Th2 cells, which promote humoral immunity and protect against extracellular parasites. Yet, little else is known of c-Maf function in CD4 cells. Here, we identify a novel role for c-Maf in regulating susceptibility to apoptosis. Overexpression of c-Maf results in increased susceptibility of CD4 cells to apoptosis induced by multiple stimuli, including growth factor withdrawal, dexamethasone, irradiation, and TCR engagement. This effect is independent of Fas or p53; however, Bcl-2 expression is reduced in c-Maf Tg CD4 cells. Immunoprecipitation and Western blot analyses demonstrate that c-Maf-c-Myb complex formation is enhanced among T cells from c-Maf Tg mice compared to non-Tg littermates following TCR engagement. Unlike non-Tg T cells, c-Myb binding to the Bcl-2 promoter is not detectable in c-Maf Tg T cells by chromatin immunoprecipitation. In reporter assays, Bcl-2 promoter activity is reduced by c-Maf in a dose-dependent manner. Furthermore, transgene-mediated Bcl-2 expression corrects the apoptosis defect observed among c-Maf Tg CD4 cells. These data suggest that c-Maf can interact with c-Myb to reduce Bcl-2 expression, thereby limiting CD4 cell survival following TCR engagement.
转录因子c-Maf对于白细胞介素-4的产生以及Th2细胞的发育至关重要，Th2细胞可促进体液免疫并抵御细胞外寄生虫。然而，关于c-Maf在CD4细胞中的功能，人们所知甚少。在此，我们确定了c-Maf在调节细胞凋亡易感性方面的新作用。c-Maf的过表达导致CD4细胞对多种刺激诱导的凋亡敏感性增加，这些刺激包括生长因子撤除、地塞米松、辐射和TCR结合。这种效应独立于Fas或p53；然而，c-Maf转基因CD4细胞中Bcl-2的表达降低。免疫沉淀和蛋白质印迹分析表明，与TCR结合后，与非转基因同窝小鼠相比，c-Maf转基因小鼠T细胞中c-Maf-c-Myb复合物的形成增强。与非转基因T细胞不同，通过染色质免疫沉淀在c-Maf转基因T细胞中检测不到c-Myb与Bcl-2启动子的结合。在报告基因检测中，c-Maf以剂量依赖性方式降低Bcl-2启动子活性。此外，转基因介导的Bcl-2表达纠正了在c-Maf转基因CD4细胞中观察到的凋亡缺陷。这些数据表明，c-Maf可与c-Myb相互作用以降低Bcl-2表达，从而限制TCR结合后CD4细胞的存活。
