O' Reilly Lorraine A, Tai Lin, Lee Lily, Kruse Elizabeth A, Grabow Stephanie, Fairlie W Douglas, Haynes Nicole M, Tarlinton David M, Zhang Jian-Guo, Belz Gabrielle T, Smyth Mark J, Bouillet Philippe, Robb Lorraine, Strasser Andreas
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Nature. 2009 Oct 1;461(7264):659-63. doi: 10.1038/nature08402.
Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL(Deltas/Deltas)) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL(Deltam/Deltam)) could not kill cells through Fas activation. FasL(Deltam/Deltam) mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL(gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL(Deltam/Deltam) mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL(gld/gld) mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.
Fas配体（FasL）是肿瘤坏死因子（TNF）细胞因子家族中一种诱导细胞凋亡的成员，其受体Fas对于终止慢性免疫反应和预防自身免疫至关重要。因此，它们基因的突变会在小鼠和人类中导致严重的淋巴结病和自身免疫性疾病。FasL的功能受质膜沉积和金属蛋白酶介导的脱落调节。在这里，我们生成了基因靶向小鼠，它们选择性地缺乏分泌型FasL（sFasL）或膜结合型FasL（mFasL），以确定细胞杀伤需要这些形式中的哪一种，并探索它们假定的非凋亡活性。缺乏sFasL的小鼠（FasL（Δs/Δs））看起来正常，其T细胞能够轻易杀死靶细胞，而缺乏mFasL的T细胞（FasL（Δm/Δm））则不能通过Fas激活来杀死细胞。FasL（Δm/Δm）小鼠出现了淋巴结病和高球蛋白血症，类似于FasL（gld/gld）小鼠，后者表达一种不能结合Fas的FasL突变形式，但令人惊讶的是，FasL（Δm/Δm）小鼠（在C57BL/6背景下）死于系统性红斑狼疮（SLE）样自身免疫性肾破坏和组织细胞肉瘤，这些疾病在FasL（gld/gld）小鼠中很少发生且发生时间要晚得多。这些结果表明，mFasL对于细胞毒性活性至关重要，是预防淋巴结病、自身免疫和癌症的守护者，而过量的sFasL似乎通过非凋亡活性促进自身免疫和肿瘤发生。
