The Level of Viral Antigen Presented by Hepatocytes Influences CD8 T-Cell Function

Abstract

CD8 T cells exert their antiviral function through cytokines and lysis of infected cells. Because hepatocytes are susceptible to noncytolytic mechanisms of viral clearance, CD8 T-cell antiviral efficiency against hepatotropic viruses has been linked to their capacity to produce gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣).On the other hand, intrahepatic cytokine production triggers the recruitment of mononuclear cells, which sustain acute and chronic liver damage. Using virus-specific CD8 T cells and human hepatocytes, we analyzed the modulation of virus-specific CD8 T-cell function after recognition peptide-pulsed or virally infected hepatocytes. We observed that hepatocyte antigen presentation was generally inefficient, and the quantity of viral antigen strongly influenced CD8 T-cell antiviral function. High levels of hepatitis B virus production induced robust IFN-␥ and TNF-␣ production in virus-specific CD8 T cells, while limiting amounts of viral antigen, both in hepatocyte-like cells and naturally infected human hepatocytes, preferentially stimulated CD8 T-cell degranulation. Our data document a mechanism where virus-specific CD8 T-cell function is influenced by the quantity of virus produced within hepatocytes.Virus-specific CD8 T cells play a major role in viral clearance and disease pathogenesis during infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) (6). The noncytopathic nature of both viruses and their ability to infect hepatocytes (1, 23, 27, 31, 39) necessitate a coordinated mechanism to reach viral clearance and avoid liver destruction (21,64). This is likely facilitated by the fact that virally infected hepatocytes are largely resistant to perforin/granzyme-mediated killing (30) but sensitive to cytokine (gamma interferon [IFN-␥] and tumor necrosis factor alpha [⌻⌵F-␣])-mediated control of viral replication (9, 21).In mouse and chimpanzee models of HBV infection, IFN-␥ produced by virus-specific CD8 T cells correlates with a profound reduction in serum and liver HBV DNA (22,23,25,63) and helps to reduce hepatocyte damage by inducing cyto-protective proteins that confer resistance to granzyme B-mediated killing (4). Similar correlations have been observed in HCVinfected humans and experimentally infected chimpanzees, where the appearance of IFN-␥-producing CD8 T cells coincides with decreases in HCV RNA (51, 52). However, intrahepatic IFN-␥ production is also responsible for triggering the recruitment of inflammatory cells to the liver, which contribute to liver pathology (2,32,45).It has often been assumed that the extent of liver damage in chronic viral hepatitis was directly proportional to the intensity of the virus-specific CD8 response. However, the frequency of circulating HBV-and HCV-specific CD8 T cells correlates more with protection than liver damage (18,29,34,35,58). Furthermore, virus-specific CD8 T cells represent a small minority of the total intrahepatic population in chronic active hepatitis B and C, and their frequencies are inversely related...

Plasmacytoid dendritic cells induce efficient stimulation of antiviral immunity in the context of chronic hepatitis B virus infection

“…Nevertheless, a strong cytotoxic response has been described in the absence of liver damage, 5 and the quantity of virus produced within hepatocytes has been shown to influence virus-specific CD8 T cell function. 34 Regulating the viral load using antiviral drugs may help control the balance between the cytotoxic and inflammatory effects of virus-specific T cells. Interestingly, specific T cell responses might even be restored in this setting.…”

Targeting Hepatitis B Virus-Infected Cells with a T-Cell Receptor-Like Antibody

“…The sensitivity of the Env183/A2 TCR-like antibody is high: not only can it detect the specific ligand on T2 cells pulsed with pM concentrations of the specific peptide, compared to CD8 T cells specific for the same HBV epitope, the TCR-like antibody also has a superior sensitivity. These characteristics, added to the fact that the HBV envelope protein is produced in high quantities on HBV-infected cells, allow this TCR-like antibody to recognize pMHC complexes on the surface of naturally infected hepatocytes despite their very low levels of HLA class I molecules expression (8) and poor antigen-processing activity (15).…”

“…Any potential in vivo applications of the TCR-like antibody require that such an antibody be able to directly recognize HBV-infected hepatocytes. Hepatocytes constitutively express low levels of HLA class I molecules (8), and their antigenprocessing machinery is inefficient for the generation of peptide/HLA class I complexes (15); thus, the quantity of the TCR-specific ligands expressed by HBV-infected hepatocytes may be much lower than the level in HBV peptide-pulsed T2 target cells.…”

Bim-mediated deletion of antigen-specific CD8+ T cells in patients unable to control HBV infection

“…Antigen that is endogenously processed and presented by hepatocytes has also been shown to induce initial proliferation followed by deletion or anergy of responding CD8 + T cells (44,45); whether this is mediated via Bim remains to be investigated. HBV-specific CD8 + T cells recognize antigen presented by HBV-infected human hepatocytes (46) and upon recognition become highly prone to apoptosis (A. Bertoletti et al, unpublished observations).…”