HLA-E expression on porcine cells: protection from human NK cytotoxicity depends on peptide loading

Human NK cells lyse porcine cells and may play an important role in the cell-mediated rejection of pig-to-human xenografts. Lysis is probably a consequence of the failure of human MHC-specific killer inhibitory receptors to recognize porcine MHC class I molecules. A majority of activated human NK cells express the HLA-E-specific inhibitory receptor CD94/NKG2A. The aim of this study was therefore to test the hypothesis that stable surface expression of HLA-E on porcine cells protects against xenogeneic NK-mediated cytotoxicity. Porcine lymphoblastoid (13 271) and endothelial (pEC) cell lines were transfected with constructs coding for HLA-E together with the leader sequence of HLA-B7 or -A2. HLA-E was correctly expressed on 13 271 cells while pEC required peptide-pulsing and/or IFN-gamma stimulation to express the HLA-E complex on the cell surface. HLA-E-expressing porcine cells were partially protected from lysis mediated by human polyclonal NK populations and completely protected from killing by NKG2Abright NK clones. In conclusion, the capability of different porcine cell types to express HLA-E on the cell surface can differ considerably depending decisively on the availability of peptides. These findings are important for the applicability of transgenic HLA-E expression as an approach to protect porcine tissues from human NK cytotoxicity.