Demonstration of virus-specific cytotoxic T lymphocytes in liver tissue in hepatitis A--a model for immunopathological reactions.

The pathogenetic mechanism leading to liver tissue injury in hepatitis caused by hepatitis A virus is unclear. We have randomly established T cell clones from liver biopsies from 4 patients with hepatitis A. A total of 578 clones was phenotypically analyzed. Whereas during the acute phase of disease CD8+ clones dominated over CD4+ clones, from a biopsy taken late after onset of clinical syndromes more CD4+ than CD8+ clones were obtained. Interestingly, in a patient with a second exacerbation of the disease, more than 20% of all clones had the CD3+ WT31- CD4- CD8- gamma delta TCR+ phenotype. Variable IFN-gamma production was observed with all types of T cell clones. All CD8+ clones had cytotoxic activity, and approximately 60% of all CD8+ clones showed specific cytotoxicity against autologous fibroblasts infected with hepatitis A virus but not with herpes simplex, adeno- or enteroviruses. These results show that the liver injury in hepatitis A is not caused by a viral cytopathogenic effect but is due to an immunopathological reaction of sensitized cytotoxic T lymphocytes against infected hepatocytes. In addition, these studies show an enrichment of CD4-8- alpha beta T cell receptor negative T lymphocytes at the site of an inflammation and suggest a role of these cells in an antiviral reaction.