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

Molecular evolution of Cide family proteins: Novel domain formation in early vertebrates and the subsequent divergence-5

Algorithm. The CIDE-N domain is indicated by a dark line on top of the alignment. The alignment of the most conserved region of 37 amino acids encompassing the EDGT signature motif is framed with a red rectangle. The signatures of Cide and Dff family proteins are framed with a green rectangle. The exon boundaries are marked by black vertical lines. (B) Sequence alignment of the CIDE-C domains of Cide family proteins found in human and mouse using MAFFT algorithm. The CIDE-C domain is indicated by a dark line on top of the alignment. The alignment of most conserved 35 amino acids is framed with a red rectangle. The exon boundaries are marked by black vertical lines.<p><b>Copyright information:</b></p><p>Taken from "Molecular evolution of Cide family proteins: Novel domain formation in early vertebrates and the subsequent divergence"</p><p>http://www.biomedcentral.com/1471-2148/8/159</p><p>BMC Evolutionary Biology 2008;8():159-159.</p><p>Published online 23 May 2008</p><p>PMCID:PMC2426694.</p><p></p