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

Abougergi, Marwan S.; Gidner, Sarah; Spady, David K.; Miller, Bruce D.; Thiele, Dwain L.

doi:10.1002/hep.20504

Cited by 24 publications

(22 citation statements)

References 46 publications

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“…Notably, however, those experiments involved the adoptive transfer of in vitro-passaged, terminally differentiated CTL clones, which may differ significantly from the primary T cell response induced in this in vivo HBV transfection model. Viral clearance in this model may use mechanism(s) more akin to the clearance of replication-deficient adenovirus in vivo, which requires Fas-and TNFR1-mediated pathways of cytolysis but is independent of perforin-and granule protease-dependent cytotoxicity mechanisms (27).…”

Section: Resultsmentioning

confidence: 99%

Immune effectors required for hepatitis B virus clearance

Yang

Althage

Chung

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

207

182

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To better define the mechanism(s) likely responsible for viral clearance during hepatitis B virus (HBV) infection, viral clearance was studied in a panel of immunodeficient mouse strains that were hydrodynamically transfected with a plasmid containing a replication-competent copy of the HBV genome. Neither B cells nor perforin were required to clear the viral DNA transcriptional template from the liver. In contrast, the template persisted for at least 60 days at high levels in NOD/Scid mice and at lower levels in the absence of CD4 + and CD8 + T cells, NK cells, Fas, IFN-gamma (IFN-γ), IFN-alpha/beta receptor (IFN-α/βR1), and TNF receptor 1 (TNFR1), indicating that each of these effectors was required to eliminate the transcriptional template from the liver. Interestingly, viral replication was ultimately terminated in all lineages except the NOD/Scid mice, suggesting the existence of redundant pathways that inhibit HBV replication. Finally, induction of a CD8 + T cell response in these animals depended on the presence of CD4 + T cells. These results are consistent with a model in which CD4 + T cells serve as master regulators of the adaptive immune response to HBV; CD8 + T cells are the key cellular effectors mediating HBV clearance from the liver, apparently by a Fas-dependent, perforinindependent process in which NK cells, IFN-γ, TNFR1, and IFN-α/βR play supporting roles. These results provide insight into the complexity of the systems involved in HBV clearance, and they suggest unique directions for analysis of the mechanism(s) responsible for HBV persistence.H epatitis B virus (HBV) is a noncytopathic human hepadnavirus that causes acute and chronic hepatitis and hepatocellular carcinoma (1). Approximately 350 million people worldwide are chronically infected by HBV, which greatly increases the risk of hepatocellular carcinoma (HCC) and causes more than 1 million deaths annually (2). Because HBV is not infectious in small animal or tissue culture models, systematic examination of the host-virus interactions during HBV infection has been difficult. The full spectrum of immunological requirements for HBV clearance is not completely defined.Our current understanding is based to a large extent on comparison of the immune responses mounted against HBV in patients who clear and who fail to clear HBV (3), experiments in which potential effectors of clearance (e.g., HBsAg-specific CD8 + T cells, recombinant IFN-γ and TNF-α) have been adoptively transferred to or induced in HBV transgenic mice (4-8), and a limited number of experiments conducted in HBVinfected chimpanzees (9, 10, 18). Collectively, these studies have led to the current model for clearance of acute HBV infection, namely (i) that viral clearance during HBV infection is associated with entry of CD8 + T cells into the liver, the production of IFN-γ, and the induction of inflammatory liver disease (reviewed in ref.3); (ii) that IFN-γ production, viral clearance, and liver disease are all impaired in the absence of CD8 + T cells (11); and (iii) that noncy...

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Section: Resultsmentioning

confidence: 99%

Immune effectors required for hepatitis B virus clearance

Yang

Althage

Chung

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

207

182

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“…Moreover, regulated expression of this specific inhibitor of granzyme B (13,18,33) in the liver accounts, at least in part, for the previously observed resistance of virally infected hepatocytes to perforin-and granzyme-dependent effector mechanisms (7) and, in turn, the greater importance of Fas and related death receptordependent cytotoxic effector mechanisms in immune-mediated injury and clearance of viral infections from the liver (8,9). Indeed, inhibition of SPI-6 expression during hepatic viral infection leads to vigorous cytopathic immune responses resulting in severalfold higher serum alanine aminotransferase levels than observed in control mice and to the development of rapid onset, fatal acute liver failure in mice with deficient SPI-6 expression (22).…”

Section: Discussionmentioning

confidence: 98%

“…Virally infected hepatocytes are resistant to killing by the perforin and granzyme-dependent cytotoxic effector pathway (7), the predominant killing pathway utilized by CTL and NK cells in clearance of noncytopathic viruses from many nonhepatic tissues. Consequently, Fas ligand and TNFR-mediated killing mechanisms play a more prominent role in clearance of viral infection from the liver than is observed during clearance of viral infections from extrahepatic sites (7)(8)(9).…”

Section: Intrahepatic Lymphocyte Expression Of Dipeptidyl Peptidase Imentioning

confidence: 99%

“…An E1-deleted, replication deficient, ␤-galactosidase encoding recombinant adenovirus AdCMV-lacZ was propagated in 293 cultures, purified on a cesium chloride gradient, and virus titers were quantified by A260:280 ratio as previously described (8,24). Mice were injected via the tail vein with 10 10 -to 10 11 optical particle units (OPU) of AdCMV-lacZ to produce hepatic adenoviral infection as previously described (7).…”

Section: Adenovirus Vectormentioning

confidence: 99%

“…␤-Galactosidase activity was quantified by measuring the rate of cleavage of 4-methylumbelliferyl-␤-D-galactoside to yield the fluorescent product 4-methylumbelliferone, as previously described (7,8).…”

Section: ␤-Galactosidase Assaymentioning

confidence: 99%

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Intrahepatic Lymphocyte Expression of Dipeptidyl Peptidase I-Processed Granzyme B and Perforin Induces Hepatocyte Expression of Serine Proteinase Inhibitor 6 (Serpinb9/SPI-6)

Stout‐Delgado

Getachew

Miller

et al. 2007

The Journal of Immunology

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Human proteinase inhibitor 9 (PI-9/serpinB9) and the murine ortholog, serine proteinase inhibitor 6 (SPI-6/serpinb9) are members of a family of intracellular serine proteinase inhibitors (serpins). PI-9 and SPI-6 expression in immune-privileged cells, APCs, and CTLs protects these cells against the actions of granzyme B, and when expressed in tumor cells or virally infected hepatocytes, confers resistance to killing by CTL and NK cells. The present studies were designed to assess the existence of any correlation between granzyme B activity in intrahepatic lymphocytes and induction of hepatic SPI-6 expression. To this end, SPI-6, PI-9, and serpinB9 homolog expression was examined in response to IFN-α treatment and during in vivo adenoviral infection of the liver. SPI-6 mRNA expression increased 10- to 100-fold in the liver after IFN-α stimulation and during the course of viral infection, whereas no significant up-regulation of SPI-8 and <5-fold increases in other PI-9/serpinB9 homolog mRNAs was observed. Increased SPI-6 gene expression during viral infection correlated with influxes of NK cells and CTL. Moreover, IFN-α-induced up-regulation of hepatocyte SPI-6 mRNA expression was not observed in NK cell-depleted mice. Additional experiments using genetically altered mice either deficient in perforin or unable to process or express granzyme B indicated that SPI-6 is selectively up-regulated in hepatocytes in response to infiltration of the liver by NK cells that express perforin and enzymatically active granzyme B.

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The role of serpinb9/serine protease inhibitor 6 in preventing granzyme B–dependent hepatotoxicity

et al. 2007

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Virally infected hepatocytes are resistant to cytotoxic lymphocyte killing by perforin-dependent and granzyme-dependent effector mechanisms. The present studies were designed to examine the role of serine protease inhibitor 6 (SPI-6) in limiting granzyme B-dependent cytotoxic effector mechanisms in the liver. SPI-6 -specific small interfering RNA (siRNA) administration to C57Bl/6J (B6) mice elicited transient alanine aminotransferase ( NK and NKT cells amplify hepatocellular injury initiated by noninfectious causes of liver injury. 6 Mice with defects in perforin/granzyme effector mechanisms have been found to have delayed clearance of a number of viral infections from extrahepatic sites but exhibit no delay in the clearance of recombinant adenoviral vectors from the liver. 7 In contrast, mice with defects in the Fas ligand (FasL)/ Fas or other death receptor pathways exhibit delayed clearance of adenoviral vectors from the liver but not from the lungs. 8 This appears to be related to the resistance of virally infected hepatocytes to killing by perforin-dependent and granzyme-dependent cytotoxic effector pathways, which results in a more prominent role for FasL and tumor necrosis factor (TNF) receptor-mediated killing mechanisms in the clearance of viral infection in the liver. 7,9,10 Human proteinase inhibitor 9 (PI-9) and the murine orthologue, serine protease inhibitor 6 (SPI-6), are members of a family of ovalbumin serpin inhibitors 11-13 present in immune-privileged cells, antigen-presenting cells, and cytotoxic T cells that afford protection against the actions of granzyme B. 14-20 The absence of SPI-6 during viral infection results in a breakdown in the cytotoxic granule integrity and increased levels of cytoplasmic granzyme B, which result in higher levels of T cell apoptosis. 21 When expressed by tumor cell lines, PI-9 12,17,22,23 and

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

Cited by 24 publications

References 46 publications

Immune effectors required for hepatitis B virus clearance

Immune effectors required for hepatitis B virus clearance

Intrahepatic Lymphocyte Expression of Dipeptidyl Peptidase I-Processed Granzyme B and Perforin Induces Hepatocyte Expression of Serine Proteinase Inhibitor 6 (Serpinb9/SPI-6)

The role of serpinb9/serine protease inhibitor 6 in preventing granzyme B–dependent hepatotoxicity

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