title: Fas and TNFR1, but not cytolytic granule-dependent mechanisms, mediate clearance of murine liver adenoviral infection.
abstract: After intravenous injection of replication-deficient adenovirus, hepatocytes are transduced and express high levels of adenovirus-encoded genes. However, adenovirally encoded gene expression is ablated rapidly by CD8+ T-cell-dependent mechanisms. Thus, this model is suitable for examining intrahepatic cytotoxic T lymphocyte (CTL) effector mechanisms. In the present studies, recombinant adenoviruses encoding secreted (human apolipoprotein A-I) or intracellular (beta-galactosidase) gene products were infused into mice with genetic deficiencies affecting the granule exocytosis-, Fas-, or tumor necrosis factor receptor 1 (TNFR1)-mediated pathways of CTL and natural killer cell effector function; the rates of clearance of adenovirus-encoded gene products were assessed. Clearance of secreted or intracellular adenoviral gene products was not delayed in perforin-deficient mice or dipeptidyl peptidase I-deficient mice, which fail to process and activate granzyme A or granzyme B. TNFR1-deficient mice also exhibited no delay in clearance of adenoviral gene products. However, adenoviral clearance from Fas-deficient mice was delayed, and such delays were much greater in mice deficient in both TNFR1 and Fas. In contrast, chimeric mice lacking both hepatic Fas and lymphocyte perforin function exhibited no greater delay in adenoviral clearance than chimeras deficient only in hepatic Fas expression. In conclusion, Fas-dependent mechanisms are required for efficient clearance of virally infected hepatocytes and, in Fas-deficient animals, TNFR1-dependent mechanisms provide an alternative mechanism for hepatic adenovirus clearance. In contrast, perforin- and granule protease-dependent cytotoxicity mechanisms play no apparent role in clearance of adenovirus from the liver.
authors.affiliation: Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9151, USA.
authors.forename: Marwan S
authors.initials: MS
authors.lastname: Abougergi
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Gidner
authors.forename: David K
authors.initials: DK
authors.lastname: Spady
authors.forename: Bonnie C
authors.initials: BC
authors.lastname: Miller
authors.forename: Dwain L
authors.initials: DL
authors.lastname: Thiele
mesh_terms: D000257:Adenoviridae Infections / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002678:Chimera; D003594:Cytoplasmic Granules / Q000378:metabolism; D005089:Exocytosis; D008099:Liver / Q000821:virology*; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000276:immunology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors; D053319:Tumor Necrosis Factor Decoy Receptors; D019014:fas Receptor / Q000276:immunology*
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D019014:fas Receptor; D054353:Perforin; C069521:recombinant human tumor necrosis factor-binding protein-1