LMP-ASSOCIATED PROTEOLYTIC ACTIVITIES AND TAP-DEPENDENT PEPTIDE-TRANSPORT FOR CLASS-I MHC MOLECULES ARE SUPPRESSED IN CELL-LINES TRANSFORMED BY THE HIGHLY ONCOGENIC ADENOVIRUS-12

Expression of class I major histocompatibility complex antigens on the surface of cells transformed by adenovirus 12 (Ad12) is generally ver y low, and correlates with the in vivo oncogenicity of this virus. In primary embryonal fibroblasts (H-2(b)) that express a transgenic swine class I antigen (PD1), Ad12-mediated transformation results in inhibi tion in transport of newly synthesized class I molecules, as well as s ignificant reduction in transporter associated with antigen presentati on (TAP) gene expression. In this report we show that reexpression of TAP molecules either by stable transfection of mouse TAP genes or by i nfection with recombinant vaccinia viruses expressing human TAP genes, only partially reconstitutes the expression and transport of the clas s I molecueles. Further analysis of Ad12-transformed cells revealed th at the expression of both LMP2 and LMP7, but not of other proteasome c omplex components, was downregulated, resulting in altered proteolytic activities of the 20S proteasomes. Reconstitution of both TAP and LMP expression resulted in complete restoration of PD1 cell surface expre ssion and enhanced expression of the endogenous H-2D(b) molecules. Des pite high expression of TAP, LMP, and class I MHC molecules encoded by recombinant vaccinia viruses, in reconstituted Ad12-transformed cells , efficient transport of H-2 class I molecules could only be achieved by treatment of the cells with gamma-interferon. These data suggest th at an additional factor(s) that is interferon-regulated plays a role i n the biosynthetic pathway of the class I complex, and that its functi on is deficient in this cell system. Thus, Ad12 viral transformation a ppears to suppress the expression of multiple genes that are important for antigen processing and presentation, which allows such transforme d cells to escape immune surveillance. This coordinate downregulation of immune response genes must likely occur through their use of common regulatory elements.