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lass="h4">Background & Aims
Perforin p
lays a centra
l ro
le in the i
mmunopathogenesis of different vira
l infections. However, its ro
le in hepatitis C virus (HCV) infection has not been fu
lly understood. Here, we ana
lyzed two c
lose
ly re
lated questions: first, is CD8+ T ce
ll-
mediated ki
lling of HCV-rep
licating hu
man hepato
ma ce
lls
mediated by perforin? Second, if so, do HCV-specific CD8+ T ce
lls obtained fro
m chronica
lly HCV infected patients express and upregu
late perforin?
lass="h4">Methods
Susceptibility of HCV-replicating human hepatoma cells to the cytotoxic pathway was tested m>in vitrom> by addition of perforin substitute streptolysin O and granzyme B and by co-culture experiments with a perforin-expressing HCV-specific CD8+ T cell clone in the presence of perforin or caspase inhibitors. HCV-specific CD8+ T cells were obtained and analyzed for perforin expression and differentiation markers m>ex vivom> from 12 chronically infected patients and 12 patients with resolved HCV infection.
lass="h4">Results
HCV-replicating human hepatoma cells were susceptible to cytotoxic killing m>in vitrom> and a dominant role of perforin in HCV-specific CD8+ T cell-mediated cytolysis was observed. However, HCV-specific CD8+ T cells obtained m>ex vivom> from chronically HCV infected patients expressed only low levels of perforin and showed an impaired ability to upregulate perforin. This was tightly linked to the distinct differentiation stage of HCV-specific CD8+ T cell differentiation m>ex vivom> since early and intermediate differentiated HCV-specific CD8+ T cells only showed weak perforin expression in contrast to late differentiated CD8+ T cells that displayed strong perforin expression.
lass="h4">Conclusions
Our results suggest that perforin plays a dominant role in CD8+ T cell-mediated lysis of HCV-replicating human hepatoma cells but that lysis may be limited in human chronic viral infection by the low perforin expression of early/intermediate differentiated HCV-specific CD8+ T cells.