Role of hepatitis B virus specific cytotoxic T cells in liver damage and viral control.

To understand the role of cytotoxic T cells in liver damage and viral control, we used human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Studies were carried out in two groups of patients, one without liver inflammation and minimal HBV replication and the other with liver damage and inflammation along with a high level of viral replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the former group, i.e., the absence of hepatic immunopathology. In the replicating viraemic group, the virus specific T cells were diluted among the liver infiltrates; although with the massive cellular infiltration that was present, the absolute number was similar. It was also shown that in the low viraemia group the reservoir of CD8+ cells present in the circulation was able to expand after specific virus recognition and that this was not detectable in highly viraemic patients with liver inflammation. These results show that inhibition of virus replication can be independent of liver damage and when the HBV-specific CD8 response is unable to control virus replication it may contribute to liver pathology not only directly but by causing recruitment of non-virus specific T cells.