Downregulation of peptide transporter genes in cell lines transformed with the highly oncogenic adenovirus 12.

Abstract

SummaryThe expression of class I major histocompatibility complex antigens on the surface of ceils transformed by adenovirus 12 (Ad12) is generally very low, and correlates with the high oncogenicity of this virus. In primary embryonal fibroblasts from transgenic mice that express both endogenous H-2 genes and a miniature swine class I gene (PD1), Ad12-mediated transformation results in suppression of cell surface expression of all class I antigens. Although class I mRNA levels of PD1 and H-2D b are similar to those in nonvirally transformed cells, recognition of newly synthesized class I molecules by a panel of monoclonal antibodies is impaired, presumably as a result of inefficient assembly and transport of the class I molecules. Class I expression can be partially induced by culturing cells at 26~ or by coculture of cells with dass I binding peptides at 37~ Analysis of steady state mRNA levels of the TAP1 and TAP2 transporter genes for Ad12-transformed cell lines revealed that they both are significantly reduced, TAP2 by about 100-fold and TAP1 by 5-10-fold. Reconstitution of PD1 and H-2D b, but not H-2K b, expression is achieved in an Ad12-transformed cell line by stable transfection with a TAP2, but not a TAP1, expression construct. From these data it may be conduded that suppressed expression of peptide transporter genes, especially TAP2, in Ad12-transformed cells inhibits cell surface expression of class I molecules. The failure to fully reconstitute H-2D b and H-2K b expression indicates that additional factors are involved in controlling class I gene expression in Ad12-transformed cells. Nevertheless, these results suggest that suppression of peptide transporter genes might be an important mechanism whereby virus-transformed cells escape immune recognition in vivo.

Organization and Functional Analysis of the Mouse Transporter Associated with Antigen Processing 2 Promoter

“…Moreover, in some tumors all of these genes are down-regulated, resulting in a loss of recognition by CTL (26). For example, Ad12-mediated transformation results in transcriptional down-regulation of class I, peptide transporter, and LMP genes (27,28). Some of these genes, such as those encoding class I heavy chains, ␤ 2 m, and TAP1, are partially suppressed, whereas transcripts encoded by TAP2, LMP2, and LMP7 genes are undetectable, as are the corresponding protein products.…”

“…The latter does not express detectable levels of TAP2 mRNA unless treated with IFNs (28). Two antisense probes were generated (Fig.…”

“…Despite evidence that TAP2 transcription is completely suppressed in some tumors (28,29), to the best of our knowledge the promoter and the regulatory elements associated with this gene have not been characterized or analyzed. We now present the initial characterization of the mouse TAP2 promoter region and 5Ј regulatory elements.…”

Immune selection and genetic sequence variation in core and envelope regions of hepatitis C virus

“…Alternative mechanisms must be sought to explain the selection of these mutants. In other chronic viral infections, viruses have been shown to express proteins that interfere with antigen processing and presentation, 37 to down regulate the expression of HLA molecules, 38 and to produce proteins that interfere with the action of host cytokines [39][40][41][42][43] and CTL responses. 44 It is possible that mutations within the envelope gene of HCV result in one or some of these actions.…”

Regulation of MHC Class I by Viruses

“…Many viral genes which encode proteins that modulate host immune responses have been identified. The E1A viral protein of Ad12 inhibits transcription of nearly all components of the MHC class I pathway, including -heavy chain, 2 m, TAP1, TAP2, LMP2, LMP7 and tapasin (Friedman and Ricciardi 1988;Rotem-Yehudar et al 1994). Similarly, the human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) also inhibit gene transcription by disrupting the IFN-induced up-regulation of the expression of genes encoding many components of the MHC class I heavy complex (Miller et al 1999).…”