Khakoo - MRC Fellowship - The influence of the liver on NK cell education: a role inn Hepatitis C?

Hepatitis C is a common viral infection of the liver. Approximately 20% of individuals are able to clear hepatitis C without treatment, however the remaining 80% are chronically infected. This can lead to liver failure and cancer. In the UK 216,000 people are infected with an estimate of 150 million worldwide. While treatments are available, 30% are still unable to clear the virus. There is no vaccine for Hepatitis C despite much work in this field. Understanding the mechanisms of viral clearance can impact vaccine design and new therapies. Whether a person is able to resolve hepatitis C depends on external factors, including alcohol use and age, but also on genetics. Patients who clear hepatitis C mount an excellent immune response to the virus. The strength of this defence system is decided by variations (polymorphisms) in genes which determine vital components of the body's immune system. We are interested in Natural Killer (NK) cells, a key player in the early immune response to hepatitis C. These cells have surface receptors, called Killer cell Immunoglobulin-like Receptors (KIRs), which interact with HLA receptors on liver cells infected by hepatitis C. Specific combinations of KIRs and their HLA pairs determine spontaneous and treatment related outcomes. The most significant genetic variable associated with Hepatitis C Virus (HCV) however is the IL28B gene, which determines components of the late immune response. We have found that the strength of these associations is influenced by the type of HCV virus present. The IL28B cascade is strongly predictive of response in patients infected with HCV type 1, whereas the KIR pathway is important for types 2 and 3. We propose that different people clear HCV via different mechanisms, i.e. either the IL28B or KIR pathway dominates depending on the patient's genetics and the type of HCV virus present. Recent data from our group suggests the strength of the IL28B system may affect the way NK cells develop. While the protective IL28B gene causes a strong release of chemicals (cytokines), particularly in the presence of HCV type 1, allowing patients to resolve HCV via this mechanism, it may weaken NK cells. Instead of allowing immature NK cells to gain KIR and grow into cytotoxic cells, a strong cytokine response may direct NK cells to develop into a hypofunctional group less able to kill cells infected by HCV. This would override the influence of protective KIR:HLA pairs, making NK cells tolerant of infection. We therefore hypothesise NK cells can be weakened during their maturation by (1) the type of HCV present; (2) the strength of chemical response induced by IL28B. We suspect the site at which this divergence occurs is the liver. Our work in liver transplantation has identified the STAT4 protein as a potential driver of this differentiation. We are keen to test this hypothesise and obtain clear definition of the above pathways. We have three specific aims. Aim 1: To study the functional maturation of NK cells in the liver and blood of non-HCV infected patients. We will obtain liver specimens from patients undergoing removal of cancer spread from the bowel to the liver and examine a sample of blood from the same patients. Aim 2: To study how STAT4 affects NK cell maturation. Aim 3: To test our model that NK cells take on different roles in HCV types 1 and 3 related to the liver cytokine environment, by taking a sample of blood from 40 patients infected with HCV. This research will be supervised by Professor Khakoo, who has published a number of landmark papers in this field and will be carried out by myself. In summary our work will link NK cell development and function with clinical outcomes in hepatitis C. Understanding how NK cell subpopulations are generated could be key to developing novel therapies or a vaccination. These insights will be important for other viral infections and liver diseases in which NK cell development is affected.