Virally infected hepatocytes are resistant to perforin-dependent CTL effector mechanisms.
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 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.
Kafrouni
M I
MI
Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Brown
G R
GR
Thiele
D L
DL
D016475:3T3 Cells; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics; D003601:Cytotoxicity Tests, Immunologic; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000378:metabolism; D053222:Fas Ligand Protein; D005822:Genetic Vectors / Q000378:metabolism; D053804:Granzymes; D006183:H-2 Antigens / Q000276:immunology; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D007763:Lac Operon / Q000235:genetics; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000821:virology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000821:virology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D019014:fas Receptor / Q000235:genetics
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D054353:Perforin; D007371:Interferon-gamma; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human