Nakamoto Y, Guidotti L G, Pasquetto V, Schreiber R D, Chisari F V
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
J Immunol. 1997 Jun 15;158(12):5692-7.
The current study was designed to explore the relative contribution of Fas ligand (FasL), perforin, IFN-gamma, and TNF-alpha-induced death pathways in the pathogenesis of CTL-induced liver disease. Hepatitis B virus-specific CTL that are genetically unable to produce either FasL, perforin, or IFN-gamma were injected into Fas-competent and Fas-deficient hepatitis B virus transgenic mice that are either sensitive or resistant to the cytopathic effects of IFN-gamma based on the extent to which their hepatocytes retain hepatitis B surface Ag (HBsAg). The results of these experiments indicate that FasL- and perforin-dependent signals are primarily responsible for the induction of liver disease in the absence of HBsAg retention, but both signaling pathways must be activated simultaneously by the CTL in order to kill the hepatocyte in vivo. In contrast, neither FasL nor perforin are required to kill hepatocytes that retain HBsAg as long as the CTL secrete IFN-gamma on antigen recognition. Finally the results indicate that, irrespective of their HBsAg content, hepatocytes are much less sensitive to destruction by TNF-alpha than by the other death pathways. While all of these death pathways appear to be operative during a normal CTL response, the current experiments suggest that the target cell determines which pathway is dominant and selects its mode of execution.
本研究旨在探讨Fas配体（FasL）、穿孔素、干扰素-γ（IFN-γ）和肿瘤坏死因子-α（TNF-α）诱导的死亡途径在细胞毒性T淋巴细胞（CTL）诱导的肝病发病机制中的相对作用。将基因上无法产生FasL、穿孔素或IFN-γ的乙型肝炎病毒特异性CTL注射到对Fas有反应和缺乏Fas的乙型肝炎病毒转基因小鼠体内，这些小鼠根据其肝细胞保留乙型肝炎表面抗原（HBsAg）的程度对IFN-γ的细胞病变效应敏感或耐受。这些实验结果表明，在没有HBsAg保留的情况下，FasL和穿孔素依赖性信号主要负责肝病的诱导，但CTL必须同时激活这两种信号通路才能在体内杀死肝细胞。相反，只要CTL在识别抗原时分泌IFN-γ，杀死保留HBsAg的肝细胞既不需要FasL也不需要穿孔素。最后，结果表明，无论肝细胞的HBsAg含量如何，其对TNF-α破坏的敏感性远低于对其他死亡途径的敏感性。虽然所有这些死亡途径在正常CTL反应中似乎都起作用，但目前的实验表明，靶细胞决定哪种途径占主导地位并选择其执行方式。
