Role of hepatic CD49a+ Natural Killer cells for hepatitis C virus infection

• Applicant: Dr. Benjamin Krämer
• Subject Area: Immunology ; Virology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 257355564

According to the world health organization (WHO), more than 170 million people are infected with hepatitis C virus (HCV). Worldwide, HCV infection is one of the major causes of chronic liver inflammation, which can result in cirrhosis, the end stage of fibrosis, and in the development of hepatocellular carcinoma after long-term course of infection.Immunogenetic studies demonstrated natural killer (NK) cells to importantly modulate the course of hepatitis C. In line with these findings, we could show that NK cells are able to block HCV replication. Furthermore, we demonstrated that an effective antiviral NK cell response was associated with a self-limited course of acute HCV infection. It should be noted that NK cells represent a very heterogeneous population of lymphocytes. Additionally, intra- and extrahepatic NK cells differ significantly with respect to phenotype and functional properties.In our preliminary studies we were able to demonstrate that hepatic CD49a+ NK cells represent a specific NK cell subset, which is characterized by a strong cytotoxic activity and cytokine secretion (IFN-gamma). Moreover, after IFN-alpha stimulation these cells showed an increased expression of the alpha-subunit of the interferon-lambda receptor (IL28RA), render these cells susceptible towards IFN-lambda stimulation. Since both IFN-lambda and IFN-gamma are considered to be central cytokines in the anti-HCV activity, our findings suggest that hepatic CD49a+ NK cells play an important role in the context of HCV infection.Therefore, it is the aim of the proposed project to characterize hepatic CD49a + NK cells in detail with respect to cytotoxicity, cytokine secretion and antiviral activity. Furthermore, the mechanisms involved in intrahepatic accumulation of CD49a+ NK cells will be studied. Finally, we will analyze the regulation of NK cells by IFN-lambda. These studies will contribute to a better understanding of the role of NK cells in hepatitis C.

• DFG Programme: Research Grants