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Suppression of adenoviral gene expression in the liver: role of innate vs adaptive immunity and their cell lysis mechanisms
Author(s) -
Minagawa Masahiro,
Kawamura Hiroki,
Liu Zhangxu,
Govindarajan Sugantha,
Dennert Gunther
Publication year - 2005
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2005.01097.x
Subject(s) - perforin , ctl* , biology , cytotoxic t cell , immunology , innate immune system , acquired immune system , major histocompatibility complex , mhc class i , tumor necrosis factor alpha , immunity , immune system , virology , cd8 , in vitro , biochemistry
Background: Injection of adenoviral constructs causes liver infection prompting immunity, which suppress viral gene expression. Innate and adaptive immunity mediate these processes raising the question which pathways are the most prominent. Methods: Adenovirus expressing the β‐galactosidase (β‐gal) gene was injected into normal and immunodeficient mice. Elimination of β‐gal‐expressing hepatocytes and increases in liver enzymes were assayed. Major histocompatibility complex (MHC) class I densities, perforin channel insertion and apoptosis by Fas and tumor necrosis factor (TNF)‐α were assayed. Results: At high virus doses, suppression of viral gene expression was as efficient in immunodeficient as in normal mice, while at low doses effects of cytotoxic T lymphocytes (CTL) were demonstrable. Despite CTL priming and elimination of infected hepatocytes no liver injury is detected. Hepatocyte MHC I densities were able to trigger CTL granule exocytosis and perforin lysis in vitro but not in vivo . This is we show is because of decreased sensitivity of hepatocytes from infected mice to perforin and increased sensitivity to Fas and TNF‐α lysis. Conclusion: Effector cells of the innate immune system are exceedingly effective in suppressing adenoviral gene expression. Perforin‐independent pathways, those mediated by TNF‐α and Fas are very efficient in hepatocytes from virus‐infected livers.