Liver-Derived Cytotoxic T Cells in Hepatitis A Virus Infection

Abstract

An autologous in vitro model was developed to analyze the immunologic cause of liver tissue injury during hepatitis A virus (HAV) infection. Human T lymphocytes infiltrating the livers of two patients with acute HAV infection were isolated from liver biopsy cores, cloned, and expanded in vitro. Procedures using a cell culture system with HAV-infected autologous skin fibroblasts demonstrated that 42% and 53% of the liver-infiltrating CD8+ clones were HAV-specific and that they kill HAV-infected skin fibroblasts in a human leukocyte antigen-restricted manner. Data show virus-specific killing by liver-infiltrating T lymphocytes in man and support the hypothesis that liver cell injury in acute HAV infection is mediated by HAV-specific CD8+ T lymphocytes and is not caused by a cytopathic effect of the virus itself.

A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

“…Since HAV infection does not itself cause major cytopathological effects in hepatic cells, the liver injury that occurs during HAV infection is presumed to result from an immune response to the virus. MHC class I-restricted CD8 + T lymphocytes that infiltrate the liver have been suggested to cause this liver injury (22). However, peripheral blood anti-HAV CD8 + CTLs peak late in infection, 2-3 weeks after onset of symptoms (23), suggesting that cells of the innate immune system play more important roles in controlling the disease.…”

The regulatory T-cell response during acute retroviral infection is locally defined and controls the magnitude and duration of the virus-specific cytotoxic T-cell response

“…In fact, there are viral infections in which the pathology induced by the host's immune response is far more detrimental than the cytopathic consequences of the virus infection itself. [6][7][8] Thus, for the health of an infected person, it might be more important to control acute CD8 ϩ T cell-mediated immunopathology than to prevent persistent viral infection. In contrast, a Treg response during a virus infection itself has to be controlled in some way or a general immunosuppression of the host would be the consequence of such a response.…”

Hepatitis A Virus Suppresses RIG-I-Mediated IRF-3 Activation To Block Induction of Beta Interferon

“…However, HAV is eliminated from the organism at later stages of the infection, and HAV infections do not result in viral persistence in the liver in vivo. This eradication of HAV from the organism, which is accompanied by massive hepatocyte destruction, is mediated mainly by the action of HAV-specific cytotoxic T lymphocytes (CTL) (18,50). In addition, data were presented demonstrating that gamma interferon (IFN-␥) is produced after HAV stimulation by HAV-specific HLA-dependent CTL in vitro and may contribute to the elimination of HAV infections in humans by inducing an antiviral state in the later course of the infection (31).…”