Virally infected hepatocytes are resistant to perforin-dependent CTL effector mechanisms
Virally infected hepatocytes are resistant to perforin-dependent CTL effector mechanisms
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DOI：
10.4049/jimmunol.167.3.1566
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发表时间：
2001-08-01
影响因子：
4.4
通讯作者：
Thiele, DL
中科院分区：
文献类型：
--
作者：
Kafrouni, MI;Brown, GR;Thiele, DL
细胞介导的细胞毒性在清除感染组织中的非细胞病变病毒中起重要作用。穿孔素依赖的细胞毒性机制在清除多个肝外器官感染中起重要作用。相反，Fas/Fas配体（FasL）介导的细胞毒性途径存在缺陷的小鼠表现出肝脏对腺病毒的清除延迟，而对肝外器官病毒感染的清除没有明显延迟。目前的研究探讨了细胞毒性效应机制在对复制缺陷重组β -半乳糖苷酶编码腺病毒（AdCMV-lacZ）的肝内免疫应答中的作用。延迟AdCMV-lacZ从fasl缺陷B6的肝脏清除。而不是缺乏穿孔素的B6。pfp（-/-）小鼠，尽管在初始肝脏CD8(+) T细胞ifn - γ或TNF反应或能够杀死adcmv - lacz感染的成纤维细胞目标的肝内细胞毒性淋巴细胞的激活方面没有显着差异。相比之下，adcmv - lacz感染的靶肝细胞对来自B6的肝内细胞毒性淋巴细胞的杀伤要敏感得多。pfp-/- than来自B6。以及fasl缺陷B6对肝细胞靶向病毒特异性杀伤的残留水平。TNF抑制可阻断gold CTL。这些结果表明，肝细胞对穿孔素依赖机制介导的细胞毒性的固有抗性使得Fas/ fasl依赖的细胞介导的细胞毒性成为ctl介导的病毒感染肝细胞杀伤的主要途径，并且解释了穿孔素不依赖的抗病毒机制在肝脏免疫应答中的更突出作用。
Cell-mediated cytotoxicity plays an important role in the clearance of noncytopathic viruses from infected tissues. Perforin-dependent cytotoxic mechanisms have been noted to play an important role in the clearance of infections from multiple extra-hepatic organs. In contrast, mice with defects in the Fas/Fas ligand (FasL)-mediated cytotoxicity pathway exhibit delayed clearance of adenovirus from the liver without apparent delay in the clearance of viral infections from extrahepatic organs. The present studies examined the role of cytotoxic effector mechanisms in intrahepatic immune responses to a replication-defective, recombinant beta -galactosidase-encoding adenovirus (AdCMV-lacZ). Delayed clearance of AdCMV-lacZ from the livers of FasL-defective B6.gld mice, but not perforin-deficient B6.pfp(-/-) mice, was noted despite no significant differences in initial hepatic CD8(+) T cell IFN-gamma or TNF responses or in activation of intrahepatic cytotoxic lymphocytes cells capable of killing AdCMV-lacZ-infected fibroblast targets. In contrast, AdCMV-lacZ-infected hepatocyte targets were far more sensitive to killing by intrahepatic cytotoxic lymphocytes from B6.pfp-/- than from B6.gld mice, and residual levels of virus-specific killing of hepatocyte targets by FasL-defective B6.gld CTL were blocked by TNF inhibition. These results suggest that inherent resistance of hepatocytes to cytotoxicity mediated by perforin-dependent mechanisms leaves Fas/FasL-dependent, cell-mediated cytotoxicity as the major pathway for CTL-mediated killing of virally infected hepatocytes and accounts for the more prominent role of perforin-independent anti-viral mechanisms in immune responses in the liver.