Rotem-Yehudar R, Groettrup M, Soza A, Kloetzel P M, Ehrlich R
Department of Cell Research and Immunology, Tel Aviv University, Israel.
J Exp Med. 1996 Feb 1;183(2):499-514. doi: 10.1084/jem.183.2.499.
Expression of class I major histocompatibility complex antigens on the surface of cells transformed by adenovirus 12 (Ad12) is generally very low, and correlates with the in vivo oncogenicity of this virus. In primary embryonal fibroblasts (H-2b) that express transgenic swine class I antigen (PD1), Ad12-mediated transformation results in inhibition in transport of newly synthesized class I molecules, as well as significant reduction in transporter associated with antigen presentation (TAP) gene expression. In this report we show that reexpression of TAP molecules either by stable transfection of mouse TAP genes or by infection with recombinant vaccinia viruses expressing human TAP genes, only partially reconstitutes the expression and transport of the class I molecules. Further analysis of Ad12-transformed cells revealed that the expression of both LMP2 and LMP7, but not of other proteasome complex 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 expression and enhanced expression of the endogenous H-2D(b) 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 that an additional factor(s) that is interferon-regulated plays a role in the biosynthetic pathway of the class I complex, and that its function is deficient in this cell system. Thus, Ad12 viral transformation appears to suppress the expression of multiple genes that are important for antigen processing and presentation, which allows such transformed cells to escape immune surveillance. This coordinate downregulation of immune response genes must likely occur through their use of common regulatory elements.
I类主要组织相容性复合体抗原在腺病毒12（Ad12）转化细胞表面的表达通常非常低，且与该病毒的体内致癌性相关。在表达转基因猪I类抗原（PD1）的原代胚胎成纤维细胞（H-2b）中，Ad12介导的转化导致新合成的I类分子运输受到抑制，以及与抗原呈递相关的转运体（TAP）基因表达显著降低。在本报告中，我们表明，通过稳定转染小鼠TAP基因或感染表达人TAP基因的重组痘苗病毒来重新表达TAP分子，仅部分重建了I类分子的表达和运输。对Ad12转化细胞的进一步分析显示，LMP2和LMP7的表达均下调，但其他蛋白酶体复合物成分的表达未下调，导致20S蛋白酶体的蛋白水解活性改变。TAP和LMP表达的重建导致PD1细胞表面表达完全恢复，并增强了重组痘苗病毒编码的内源性H-2D(b)分子的表达，在重建的Ad12转化细胞中，只有通过用γ干扰素处理细胞才能实现H-2 I类分子的有效运输。这些数据表明，一种受干扰素调节的额外因子在I类复合物的生物合成途径中起作用，并且其功能在该细胞系统中存在缺陷。因此，Ad12病毒转化似乎抑制了对抗原加工和呈递很重要的多个基因的表达，这使得此类转化细胞能够逃避免疫监视。免疫反应基因的这种协同下调很可能是通过它们使用共同的调控元件来实现的。
