The role of TNF–TNFR2 interactions in generation of CTL responses and clearance of hepatic adenovirus infection

Kafrouni, Michel I.; Brown, Geri; Thiele, Dwain L.

doi:10.1189/jlb.0103035

Cited by 50 publications

(48 citation statements)

References 38 publications

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“…A study by another group confirmed that TNFR2 functioned as a costimulator for human T cells (22). Another study found that TNFR2 Ϫ/Ϫ mice display delayed clearance of replication-deficient adenovirus that correlated with decreased adenovirus-specific CTL activity of intrahepatic lymphocytes, indicating that TNFR2 facilitates generation of CTL effector function for antiviral immune responses in the liver in vivo (23). These studies indicate that TNFR2 functions in T cells as an important costimulator for the differentiation program triggered by TCR-mediated stimulation.…”

mentioning

confidence: 78%

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Kim

Priatel

Teh

et al. 2006

The Journal of Immunology

139

130

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Naive T cells require costimulation for robust Ag-driven differentiation and survival. Members of the TNFR family have been shown to provide costimulatory signals conferring survival at distinct phases of the T cell response. In this study, we show that CD4 and CD8 T cells depend on TNFR type 2 (p75) for survival during clonal expansion, allowing larger accumulation of effector cells and conferring protection from apoptosis for a robust memory pool in vivo. We demonstrate using the MHC class I-restricted 2C TCR and MHC class II-restricted AND TCR transgenic systems that TNFR2 regulates the threshold for clonal expansion of CD4 and CD8 T cell subsets in response to cognate Ag. Using a novel recombinant Listeria monocytogenes (rLM) expressing a secreted form of the 2C agonist peptide (SIY) to investigate the role of TNFR2 for T cell immunity in vivo, we found that TNFR2 controls the survival and accumulation of effector cells during the primary response. TNFR2−/− CD8 T cells exhibit loss of protection from apoptosis that is correlated with diminished survivin and Bcl-2 expression. Null mutant mice were more susceptible to rLM-SIY challenge at high doses of primary infection, correlating with impaired LM-specific T cell response in the absence of TNFR2-mediated costimulation. Moreover, the resulting memory pools specific for SIY and listeriolysin O epitopes derived from rLM-SIY were diminished in TNFR2−/− mice. Thus, examination of Ag-driven T cell responses revealed a hitherto unknown costimulatory function for TNFR2 in regulating T cell survival during the differentiation program elicited by intracellular pathogen in vivo.

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mentioning

confidence: 78%

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

Kim

Priatel

Teh

et al. 2006

The Journal of Immunology

139

130

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“…␤-Galactosidase activity in liver tissue homogenates was quantified by measuring the rate of cleavage of 4-methylumbelliferyl-␤-D-galactoside to yield the fluorescent product 4-methylumbelliferone as previously described. 20,24 For each sample, the reported value is an average of dilutions falling in the assay linear range.…”

Section: Methodsmentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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

Abougergi¹,

Gidner²,

Spady³

et al. 2005

Hepatology

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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 (␤-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.

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“…Human PBMC, human Huh-7 hepatoma cells (22), and mouse AML-12 cells (23) were cultured in 25 cm 2 tissue culture flasks (Costar, Cambridge, MA) at 37°C in a humidified, 5% CO 2 atmosphere in RPMI 1640 medium (Huh-7 cells; BioWhittaker, Walkersville, MD) or equal proportions of DMEM and F12 medium (AML-12 cells; BioWhittaker), supplemented with 10% FBS (Life Technologies, Gaithersburg, MD), 1 mM pyruvate, 100 g/ml streptomycin, and 200 U/ml penicillin G. PBMC cultures were supplemented with 0.5 g/ml PHA (Roche Molecular Biochemicals, Indianapolis, IN) for 3 days to activate T lymphocytes or with 100 U/ml rIL-2 for 2 days to generate lymphokine-activated killer (LAK) cells. Anti-H-2 q -specific CTL were generated in 5-day MLC containing 12 ϫ 10 6 responder spleen cells from C57BL/6 background (H-2 b ) mice and equal numbers of irradiated FVB-NJ (H-2 q ) stimulator spleen cells in 6 ml of RPMI 1640 medium supplemented with 10% FBS as previously described (10,12).…”

Section: Cells and Culture Conditionsmentioning

confidence: 99%

Antiviral Cytokines Induce Hepatic Expression of the Granzyme B Inhibitors, Proteinase Inhibitor 9 and Serine Proteinase Inhibitor 6

Barrie

Stout

Abougergi

et al. 2004

The Journal of Immunology

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Expression of the granzyme B inhibitors, human proteinase inhibitor 9 (PI-9), or the murine orthologue, serine proteinase inhibitor 6 (SPI-6), confers resistance to CTL or NK killing by perforin- and granzyme-dependent effector mechanisms. In light of prior studies indicating that virally infected hepatocytes are selectively resistant to this CTL effector mechanism, the present studies investigated PI-9 and SPI-6 expression in hepatocytes and hepatoma cells in response to adenoviral infection and to cytokines produced during antiviral immune responses. Neither PI-9 nor SPI-6 expression was detected by immunoblotting in uninfected murine or human hepatocytes. Similarly, human Huh-7 hepatoma cells were found to express only very low levels of PI-9 relative to levels detected in perforin- and granzyme-resistant CTL or lymphokine-activated killer cells. Following in vivo adenoviral infection or in vitro culture with IFN-αβ or IFN-γ, SPI-6 expression was induced in murine hepatocytes. Similarly, after culture with IFN-α, induction of PI-9 mRNA and protein expression was observed in human hepatocytes and Huh-7 cells. IFN-γ and TNF-α also induced 4- to 10-fold higher levels of PI-9 mRNA expression in Huh-7 cells, whereas levels of mRNA encoding a related serine proteinase inhibitor, proteinase inhibitor 8, were unaffected by culture of Huh-7 cells with IFN-α, IFN-γ, or TNF-α. These findings indicate that cytokines that promote antiviral cytopathic responses also regulate expression of the cytoprotective molecules, PI-9 and SPI-6, in hepatocytes that are potential targets of CTL and NK effector mechanisms.

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The role of TNF–TNFR2 interactions in generation of CTL responses and clearance of hepatic adenovirus infection

Cited by 50 publications

References 38 publications

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

TNF Receptor Type 2 (p75) Functions as a Costimulator for Antigen-Driven T Cell Responses In Vivo

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

Antiviral Cytokines Induce Hepatic Expression of the Granzyme B Inhibitors, Proteinase Inhibitor 9 and Serine Proteinase Inhibitor 6

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