Pathogenic Interaction between Natural Killer (NK) and T cells in chronic Hepatitis B Virus Infection

Hepatitis B virus (HBV) persistently infects more than 400 million people worldwide. Chronic (longterm) infection carries a risk of serious complications including severe liver disease and liver cancer and is responsible for more than 1 million deaths per year. The body combats the virus using a number of specialised cell types. The main cell type fighting the virus, called the T cell, is severely impaired in chronic infection. In this study we will be looking at the ability of another type of cell called Natural Killer (NK) cell, to kill the beneficial T cells. NK cells have already been shown to be able to cause liver damage in viral hepatitis and we have found increased numbers in patients with chronic hepatitis B. Malfunctioning NK cells may also attack healthy T cells, causing chronic disease instead of fighting it. The purpose of this study is to identify the possible NK cell-mediated death pathways leading to T cell ‘exhaustion‘. We will use blood and liver samples obtained during routine clinical care of patients infected with HBV following informed consent. Blocking these harmful death pathways will boost the immune system leading to improved viral control and prevention of chronic disease and liver damage.

Aims and Objectives: Accumulating data indicate that Natural Killer (NK) cells play an important role in shaping adaptive immunity. Our group has demonstrated an enrichment of activated CD56bright NK cells expressing the TNF-related apoptosis-inducing ligand (TRAIL) in the HBV-infected liver and identified a role for natural killer (NK) cells in amplifying liver damage through the TRAIL pathway (Dunn JEM 2007). Recent studies and preliminary data have highlighted the potential for NK cells to delete autologous T cells when T cell activation overrides the physiological protection against this. We postulate that activated HBV-specific T cells become susceptible to deletion by pathogenic intrahepatic NK cells in the setting of the inflamed HBV-infected liver. NK cell-mediated killing could thereby constitute a novel mechanism contributing to the profound virus-specific T cell depletion in chronic HBV infection. We aim to investigate whether NK and virus-specific T cells upregulate the appropriate receptor-ligand pairs to allow NK cell-mediated T cell deletion in active HBV infection.
Design and Methodology: We will concentrate on TRAIL and NKG2D as potential pathways of deletion and assess the level of expression of NK and T death receptor-ligand pairs according to disease activity. Using surplus tissue from diagnostic liver biopsies or explants, we will investigate whether there is enhanced expression of death receptor-ligand pairs in the intrahepatic compared to the peripheral compartment. Functional experiments with blocking antibodies and NK cell depletion will allow us to determine the capacity of NK cells to kill autologous virus-specific T cells from patients with different disease profiles, and to investigate whether HBV-specific T cells are more susceptible than T cells of other specificities in the same patients. A longitudinal sub-study of patients commencing antiviral therapy will examine its potential to reverse any pathogenic NK-T cell interactions.
Scientific and medical opportunities: Chronic infection with HBV causes cirrhosis and hepatocellular carcinoma, remaining one of the top ten causes of mortality worldwide. This work could lead to the development of agents to block pathogenic NK cell interactions at the time of therapeutic vaccination, enabling reconstitution of sustained virus-specific T cell responses whilst limiting liver damage. Insights from this study of NK cells in chronic HBV infection could be applied to other hepatotropic pathogens (HCV, malaria) and tumours and will extend knowledge of innate-adaptive immune interactions.