Virally Infected Hepatocytes Are Resistant to Perforin-Dependent CTL Effector Mechanisms

Abstract

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 β-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-γ 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.

Significance of Alterations in PBMC Immunophenotype of Children with Chronic Viral Hepatitis C – the Role of Dendritic Cells

“…It might be in line with findings of Kafrouni et al [16]. These authors reported that virally infected hepatocytes become resistant to cytotoxic effector cells.…”

Hepatitis C virus infection and apoptosis

“…Similar to deathligand induced apoptosis, granzyme B-mediated apoptosis largely depends on caspase activation and the sensitivity of the target cell. Hepatocytes seem resistant to granzyme B mediated cell death, and CTL killing of infected hepatocytes is perforin/granzyme B-independent [29,64] . Therefore, a contribution of this apoptosis mechanism in patients with viral hepatitis is very unlikely.…”

Fas and TNFR1, but not cytolytic granule-dependent mechanisms, mediate clearance of murine liver adenoviral infection

“…In contrast, marked delay in hepatic adenoviral infection is noted in mice deficient in Fas, FasL, or TNF expression. 13,20,[23][24][25] However, mice with isolated defects in expression of TNFR1, the major mediator of TNF-induced apoptosis, clear hepatic adenoviral infection at rates similar to those in wild-type mice, whereas mice with defects in either TNF or tumor necrosis factor receptor 2 expression exhibit delays in adenoviral clearance that seem to be related to diminished activation of intrahepatic FasL-expressing CTL. 24 Thus, results of prior studies suggest that among the various CTL effector pathways, FasL/Fas-mediated cytotoxic effector mechanisms play the most prominent role in clearance of hepatic viral infections, 20,24 whereas the potential role of other cytotoxic effector mechanisms remains unclear.…”

“…19 Despite the prominent role that the perforin-and granzyme-mediated granule exocytosis pathway plays in the clearance of a variety of extrahepatic viral infections, mice with isolated perforin deficiency do not exhibit deficiency in clearance of hepatic adenoviral infection. 20 Moreover, despite readily apparent delays in clearance of murine cytomegalovirus from the spleen 21 and salivary gland 22 of perforin-deficient mice, there is no delay in clearance of murine cytomegalovirus from the liver 21 of these mice. In contrast, marked delay in hepatic adenoviral infection is noted in mice deficient in Fas, FasL, or TNF expression.…”