Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, UPV/EHU, 48080 Bilbao, Spain.
Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain.
Int J Mol Sci. 2021 Dec 28;23(1):311. doi: 10.3390/ijms23010311.
Targeted disruption of E2f2 in mice causes T-cell hyperactivation and a disproportionate cell cycle entry upon stimulation. However, mice do not develop a lymphoproliferative condition. We report that E2f2 plays a Fas-dependent anti-apoptotic function in vitro and in vivo. TCR-stimulated murine T cells overexpress the proapoptotic genes and and exhibit enhanced apoptosis, which is prevented by treatment with neutralizing anti-FasL antibodies. p53 pathway is activated in TCR-stimulated lymphocytes, but targeted disruption of p53 in mice does not abrogate Fas/FasL expression or apoptosis, implying a p53-independent apoptotic mechanism. We show that E2f2 is recruited to and gene promoters to repress their expression. in vivo, mice are prone to develop immune-mediated liver injury owing to an aberrant lymphoid Fas/FasL activation. Taken together, our results suggest that E2f2-dependent inhibition of Fas/FasL pathway may play a direct role in limiting the development of immune-mediated pathologies.
靶向敲除小鼠 E2f2 可导致 T 细胞过度激活，并在刺激后不成比例地进入细胞周期。然而，这些小鼠并没有发展出淋巴增生性疾病。我们报告称，E2f2 在体外和体内发挥 Fas 依赖性抗凋亡功能。TCR 刺激的小鼠 T 细胞过度表达促凋亡基因 和 ，并表现出增强的细胞凋亡，这可以通过用中和性抗 FasL 抗体处理来预防。p53 通路在 TCR 刺激的淋巴细胞中被激活，但在 小鼠中靶向敲除 p53 并不能消除 Fas/FasL 的表达或凋亡，这表明存在一种不依赖 p53 的凋亡机制。我们表明，E2f2 被招募到 和 基因启动子以抑制它们的表达。在体内，由于异常的淋巴样 Fas/FasL 激活， 小鼠易发生免疫介导的肝损伤。总之，我们的结果表明，E2f2 依赖性抑制 Fas/FasL 通路可能在限制免疫介导的病理发展中发挥直接作用。
