Hughes Peter D, Belz Gabrielle T, Fortner Karen A, Budd Ralph C, Strasser Andreas, Bouillet Philippe
Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Melbourne 3050, Australia.
Immunity. 2008 Feb;28(2):197-205. doi: 10.1016/j.immuni.2007.12.017.
Apoptotic death of T lymphocytes is critical for shutdown of immune responses and hemopoietic cell homeostasis. Both death receptor (Fas) activation and mitochondrial apoptosis triggered by the BH3-only protein Bim have been implicated in the killing of antigen-stimulated T cells. We examined mice lacking the gene encoding Bim (Bcl2l11) and with the inactivating lpr mutation in the gene encoding Fas (Fas), designated Bcl2l11(-/-)Fas(lpr/lpr) mice. Shutdown of an acute T cell response to herpes simplex virus involved only Bim with no contribution by Fas, whereas both pathways synergized in killing antigen-stimulated T cells in chronic infection with murine gamma-herpesvirus. Bcl2l11(-/-)Fas(lpr/lpr) mice developed remarkably enhanced and accelerated fatal lymphadenopathy and autoimmunity compared to mice lacking only one of these apoptosis inducers. These results identify critical overlapping roles for Fas and Bim in T cell death in immune response shutdown and prevention of immunopathology and thereby resolve a long-standing controversy.
T淋巴细胞的凋亡性死亡对于免疫反应的终止和造血细胞的稳态至关重要。死亡受体（Fas）激活以及仅含BH3结构域的蛋白Bim触发的线粒体凋亡均与抗原刺激的T细胞杀伤有关。我们研究了缺乏编码Bim的基因（Bcl2l11）且编码Fas的基因（Fas）存在失活lpr突变的小鼠，即Bcl2l11(-/-)Fas(lpr/lpr)小鼠。急性T细胞对单纯疱疹病毒反应的终止仅涉及Bim，Fas无作用，而在小鼠γ-疱疹病毒慢性感染中，两条途径协同作用杀伤抗原刺激的T细胞。与仅缺乏其中一种凋亡诱导因子的小鼠相比，Bcl2l11(-/-)Fas(lpr/lpr)小鼠出现了显著增强和加速的致命性淋巴结病及自身免疫。这些结果确定了Fas和Bim在免疫反应终止和预防免疫病理中T细胞死亡方面的关键重叠作用，从而解决了一个长期存在的争议。
