Intrahepatic T Cells in Hepatitis B

Clearance of the hepatitis B virus (HBV), a noncytopathic double-stranded DNA virus, requires the coordinated response of innate and adaptive, humoral and cellular immune systems. In more than 90% of immunocompetent adults who become infected, this immune response is quite vigorous, resulting in acute, self-limited hepatitis with rapid reduction of viral load and long-lasting, protective humoral and cellular immunity. However, in 5% of HBV-infected immunocompetent adults, and most cases of vertical transmission of HBV, persistent infection and chronic necroinflammatory liver disease evolve which may eventually lead to liver cirrhosis and hepatocellular carcinoma. In HBV infection, the cellular immune response is thought to contribute to both viral clearance and liver cell injury. These two opposing functions have even been attributed to the same cell: upon cognate recognition of viral peptides on MHC class I molecules of HBV-infected cells, CD8 1 T cells acquire the capacity to either cure HBVinfected cells via noncytopathic, cytokine-mediated inhibition of HBV replication or to destroy them via perforin-, Fas ligand (FasL)-, and TNFa –mediated death pathways. Both effector functions have been observed during resolution of acute hepatitis B (1). Individuals with acute, self-limited HBV infection characteristically mount a vigorous, polyclonal, and multispecific Th and CTL response to epitopes within the HBV envelope (HBe), nucleocapsid, and polymerase proteins that is readily detectable in the peripheral blood. This response coincides with the maximum elevation of serum alanine aminotransferase (ALT) levels (2) and precedes clearance of HBe and surface (HBs) antigens and development of neutralizing antibodies (3). In contrast, the HBV-specific immune response is weak or undetectable in the blood of chronically infected patients, although individual, HBVspecific T cell clones have been isolated and expanded from liver biopsies (4, 5). Since HBV is considered a noncytopathic virus and the degree of the intrahepatic inflammatory leukocytic infiltrate is regarded as the histologic hallmark of the severity of chronic hepatitis B, it has been postulated that the HBV-specific immune response is too weak to eliminate HBV from all infected hepatocytes, but sufficiently strong to continuously destroy HBV-infected hepatocytes and to induce chronic inflammatory liver in persistently infected individuals. The reason for this inefficient, yet harmful nature of the cellular immune response in chronic hepatitis B is currently not known. Is the absolute number of intrahepatic and circulating HBV-specific T cells too low to clear HBV early in the infection? Are HBV-specific T cells anergized by high viral load? Do intrahepatic HBV-specific T cells exert different effector functions in chronically infected patients than in those who control HBV replication? Do intrahepatic T cells recognize different, e.g., subdominant, HBV epitopes in chronically infected patients? Or are functional HBV-specific T cells antagonized by emerging HBV mutants? Finding answers to these questions has been hampered by the fact that HBV does not grow in tissue culture and that the chimpanzee is the only animal that can be infected with the virus. HBV-specific T cells have been isolated from liver biopsies of chronically infected patients, but phenotypic and functional characterization generally required extensive in vitro expansion (4, 5). This technique unavoidably introduced a selection bias for T cells that could be expanded in tissue culture, and thus, allowed neither correct quantitation of HBV-specific T cells within the intrahepatic infiltrate nor direct ex vivo assessment of T cell function.