The Role of Virus-Specific Cd8+ Cells in Liver Damage and Viral Control during Persistent Hepatitis B Virus Infection

Abstract

Hepatitis B virus (HBV) is a noncytopathic virus, and the recognition of infected hepatocytes by HBV-specific CD8 cells has been assumed to be the central mechanism causing both liver damage and virus control. To understand the role of cytotoxic T cells in the pathogenesis of HBV infection, we used functional assays that require T cell expansion in vitro and human histocompatibility leukocyte antigen (HLA)-peptide tetramers that allow direct ex vivo quantification of circulating and liver-infiltrating HBV-specific CD8 cells. Two groups of patients with persistent HBV infection were studied: one without liver inflammation and HBV replication, the other with liver inflammation and a high level of HBV replication. Contrary to expectation, a high frequency of intrahepatic HBV-specific CD8 cells was found in the absence of hepatic immunopathology. In contrast, virus-specific T cells were more diluted among liver infiltrates in viremic patients, but their absolute number was similar because of the massive cellular infiltration. Furthermore, inhibition of HBV replication was associated with the presence of a circulating reservoir of CD8+ cells able to expand after specific virus recognition that was not detectable in highly viremic patients with liver inflammation.These results show that in the presence of an effective HBV-specific CD8 response, inhibition of virus replication can be independent of liver damage. When the HBV-specific CD8 response is unable to control virus replication, it may contribute to liver pathology not only directly but by causing the recruitment of nonvirus-specific T cells.

Effects of antiviral therapy on the cellular immune response in patients with chronic hepatitis B

“…Previous studies in humans, chimpanzees and HBV transgenic mice reveal that intrahepatic HBV-specific T cells, as well as natural killer (NK) and NKT cells, are important in viral clearance and disease pathogenesis during HBV infection. A vigorous HBV-specific T cell response is readily detectable in the liver of AHB patients, but due to functional or quantitative differences in this response, chronically infected patients are unable to terminate the infection (19,20). Our results, based on peripheral blood samples, are in agreement with the studies already mentioned.…”

Virus-Specific CD8+ T Cells in the Liver: Armed and Ready to Kill

“…Early studies pointed to the liver as a site for T cell contraction (10 -13) that is essential for the immune system to maintain homeostasis (14). Despite this protective capacity, antiviral CD8 ϩ T cells can also promote tissue destruction and exacerbate disease (15)(16)(17)(18), including the induction of hepatitis during influenza infection though there is no detectable viral Ag in the liver (19,20). Accordingly, programmed contraction and exhaustion of Ag-specific CD8 ϩ T cells during chronic infection may circumvent possible immunopathology.…”

Virus‐specific CD8+ T lymphocytes within the normal human liver

“…Broadly, CD8 + T cells may maintain, or revert to, the expression of markers associated with lymph node homing (CD62L, CCR7), described as central memory T cells, with less immediate protective capacity, but strong proliferative capacity [6]. Conversely, effector memory T cells lack these markers [6] and, in murine studies, appear to have an important protective role, particularly within the tissue compartment [7,8]. In man, the more 'mature' effector memory cells lose certain cell surface markers (CD27, CD28) as they acquire intracellular perforin [9,10].…”