The genetic regulation of natural killer-mediated cell lysis in xenograft

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We have investigated the effect of HLA-G and HLA-E to NK-mediated direct cytotoxicity, using hamster ovarian tumor cells (CHO) or swine endothelial cell (SEC) transfectants with these molecules.At first, cDNA of human full-length HLA-G (G1 and G3), HLA-E and β2-macroglobulin were prepared and subcloned into the pCAGGS (β-actin promoter).The surface expression of HLA-G (G1) and β2-macroglobulin were confirmed. In addition, co-transfection of β2-microglobulin with HLA-G1 enhanced the level of expression by several times. On the other hand, HLA-G3 was not expressed on the SEC surface.Concerning HLA-E, the expression was checked by FACS and northern blot. The signal peptide of HLA-E was substituted with that of HLA-G for certain expression.Amelioration of NK cell-mediated lysis by the transfectant molecules on CHO or SEC was then tested as an in vitro delayed-type rejection model of a discordant xenograft. HLA-G1 and HLA-E significantly suppressed the NK cell mediated SEC lysis.The expression of HLA-G and/or HLA-E on the cell surface serves as a new approach in overcoming NK-mediated immunity to xenografts.