Of Natural Killer cells and Hepatitis C Virus

Natural Killer (NK) cells are important effector cells in Hepatitis C Virus (HCV) infection, a virus that chronically infects around 2.5% of the world population and is a major cause of liver disease and hepatocellular carcinoma. The exact mechanisms, however, through which NK cells are activated in response to HCV remain elusive. Using the well-established HCV replicon cell-culture model we show that after co- culture of HCV replicon-carrying hepatocytes with peripheral blood mononuclear cells (PBMCs), NK cells increase expression of the high-affinity IL-2 receptor chain CD25, proliferate rapidly and produce IFN-gamma. Activation of NK cells was dependent on IL-2, most likely produced by T cells and on cell-cell contact mediated signals from monocytes. Monocytes from replicon-carrying co-cultures showed increased expression of OX40L, a member of the tumor necrosis factor family and concurrently its receptor OX40 was increased on NK cells. Blocking of OX40L in those co-cultures, as well as depletion of CD14+ monocytes abrogated the virus-induced activation and effector functions of NK cells. Together, our data reveals a novel mechanism of monocyte mediated NK cell activation against virus-infected cells involving the OX40/OX40L axis with potential relevance for therapeutic intervention by e.g. agonistic antibodies against OX40, which are already tested in cancer therapy