An extra molecule in addition to human tapsin is required for surface expression of β2m linked HLA-B4402 on murine cell

Murine MHC class I can be readily expressed on the surface of human cell lines, but human class I molecules are expressed on mouse cells at a reduced level. Both human beta-2-microglobulin (β2m) and tapasin (Tpn) have been demonstrated to be required for proper human MHC class I surface expression. Here we report that besides β2m and tapasin, an extra unidentified component is also critical for the expression of certain human class I alleles. By covalently linking HLA-B4402 heavy chain to β2m (β2m–B44) a pre-assembled class I molecule has been created, which can be efficiently expressed and travel to the surface in human cells. In spite of being able to express inside cells, the linked β2m–B44 molecule does not express on the surface of a murine fibroblast. Further investigation shows that lack of appearance on the surface is not due to quick degradation of unloaded class I, since provision of HLA-B4402 binding peptide could not rescue impaired surface expression. Co-expression with human tapasin does not rescue the defect excluding tapasin as the critical component for expression and indicating that a novel component of human origin is required for efficient surface expression of β2m–B44 in murine cells. Surprisingly, not only did the β2m–B44 construct fail to express on murine cells but also the surface expression of native murine MHC class I Kb was greatly reduced in transfected cells. It is likely that the expressed linked chain competitively associates with a component of class I processing in murine cells, reducing the exit rate of assembled mouse class I molecules. The results together suggest an unknown mechanism, which leads to the trapping of class I molecules in the ER.