Peppa, D; (2013) Antiviral and immunoregulatory roles of natural killer cells in chronic hepatitis B virus infection. Doctoral thesis (PhD), UCL (University College London).

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Abstract

Persistent infection with hepatitis B virus (HBV) is a global health burden accounting for more than a 1 million deaths worldwide. Much work has focused on the failure of the adaptive immune response in persistent HBV infection. In contrast innate responses remain poorly characterised. Accumulating evidence indicates the involvement of NK cells in the control of viral infections and shaping of adaptive immunity. Here we investigated the antiviral and immunoregulatory potential of NK cells in chronic Hepatitis B virus infection (CHB). The combination of immunosuppressive cytokines seen in CHB suppresses the non-cytolytic antiviral function of NK cells, whilst maintaining TRAIL mediated killing, which has been associated with hepatocyte apoptosis. Our findings further implicate NK cells in the down-regulation of antiviral T cells, which are profoundly diminished and prone to apoptosis in CHB. Our data show that in vitro depletion of NK cells results in recovery of HBV-specific CD8 T cells, an effect that was not observed for control virus responses. When NK cells were depleted or not in contact with T cells, the degree of caspase activation in HBV-specific T cells was decreased, supporting a direct and contact dependent NK cell effect on virus-specific CD8 T cell survival involving induction of apoptosis. NK cells, the predominant population of TRAIL expressing cells in the HBV infected liver, were found in intimate contact with T cells within the liver sinusoidal spaces. The observed upregulation of the death receptor, TRAIL-R2 on CD8 T cells, likely imposed by the intrahepatic milieu in HBV infection may sensitise them to apoptosis. Our findings illustrate an important and novel mechanism of immune dysregulation contributing to viral persistence in humans. The potential to selectively deviate NK cells from pathogenic roles, whilst augmenting antiviral functions could improve HBV control and enhance the design of future therapeutic strategies.

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