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Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390
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 extrahepatic 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 
-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-
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.
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