Expression of histocompatibility antigens H-2K, -D, and -L is reduced in adenovirus-12-transformed mouse cells and is restored by interferon gamma (original) (raw)
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Proceedings of the National Academy of Sciences, 1986
Inbred hamster and mouse cells transformed by the nononcogenic adenovirus (Ad) serotypes, Ad2 and Ad5, are nontumorigenic in syngeneic adult animals, while cells from these species transformed by the highly oncogenic Ad12 are tumorigenic in such rodents. By immunoprecipitation and flow cytometry, cells from four of six Ad2- and Ad5-transformed hamster and mouse lines expressed high levels of cell-surface class I major histocompatibility complex (MHC) antigens, while cells from two of these six lines expressed low levels of cell-surface class I MHC antigens. The levels of class I MHC proteins expressed by cells from these latter two lines were comparable to the levels of cell-surface class I MHC proteins expressed by cells from Ad12-transformed hamster and mouse lines. Moreover, an Ad2-transformed line that had become highly oncogenic after in vivo adaptation showed the same high level of MHC expression as the nononcogenic parent. The amounts of class I mRNA, analyzed by RNA blotting...
Tumorigenicity of cells transformed by adenovirus type 12 by evasion of T-cell immunity
1983
Evidence is presented that cells transformed by adenovirus type 12 are oncogenic because they escape from T-cell immunity. This effect is brought about by reducing the expression of class I transplantation antigens and is a function of the protein translated from the 13S mRNA, transcribed from early region la. These findings establish a novel mechanism by which transformed cells can acquire an oncogenic phenotype. ADENOvIRUS-transformed rodent cells exhibit variable degrees of oncogenicity, depending on the adenovirus species used for transformation: rat cells transformed by the highly oncogenic adenovirus 12 (Ad12) are highly oncogenic in the syngeneic host', whereas rat cells transformed by the nononcogenic adenoviruses, for example Ad2 and Ad5, are rarely tumorigenic in immunocompetent syngeneic rats2. It has been proposed that cells transformed by the non-oncogenic adenoviruses fail to form tumours because they are more antigenic than are cells transformed by oncogenic adenoviruses and
Journal of Virology, 1994
Chimeric adenovirus type 5 (Ad5)/Ad12 early region 1A (E1A) genes were used to transform primary baby rat kidney cells in cooperation with Ad12 E1B, and the resulting cell lines were assayed for tumorigenicity in syngeneic rats. It was found that lines were nontumorigenic when transformed by hybrid E1A genes consisting of the amino-terminal 80 amino acids from Ad12 including conserved region 1 (CR1), with the remaining portion from Ad5. In contrast, cell lines transformed by hybrids containing Ad12 E1A sequences from the amino terminus to the leftmost border of CR3 or beyond were tumorigenic. To extend these results, sequences spanning CR2 and CR3 of Ad5 E1A were replaced with the homologous regions of Ad12 E1A and additional transformed cell lines were established. These lines were weakly-to-moderately tumorigenic, suggesting that Ad12 E1A sequences between CR2 and CR3 may be involved in tumorigenicity but are not the sole factors influencing it. Interestingly, examination of an E1...
The level of expression of class-I MHC antigens in adenovirus-transformed human cell lines
International Journal of Cancer, 1987
The level of expression of the class-I major histocompatibil-19 and 54kDa. The El region encompasses those viral genes ity (MHC) antigen was determined in a series of human em-expressed first following lytic infection and is also that area bryo cell lines transformed with either adenovirus I2 (Ad 12) responsible for the acquisition and maintenance of the transearly region ' (El) Or adenovirus formed phenotype (for reviews see Bernards and van der Eb, 1987). activated N-ras DNA. MHC class-I antigen expression was greatly reduced in all Ad I 2 transformants, compared to primary cells. Expression was also reduced in the Ad 5 cell lines In view of the interesting data obtained with adenovirustransformed with E I A and EIB DNA, but levels were near transformed rodent cell systems, we have undertaken an extennormal in those lines with only E I A D N A present. Amounts sive investigation of the level of expression of MHC c1ass-I of MHC class-I antigen on the cell surface. as determined by antigen in a series of human cell lines produced after transfor-RIA and FACS analysis, generally reflected total cellular levels mation with either Ad 12 or Ad 5 EI DNA. I,, addition, the as determined by Western blotting. Expression of p2 microwas also much reduced in those cell lines with low effect on MHC of substituting the activated N-ras gene for the levels of M H C class-I antigen. The treatment of primary cells and all the transformants with human y-interferon resulted in increased expression of HLA on the cell surface. Infection of primary human cells with Ad I 2 or with a series of Ad I2 mutants did not have any effect on the MHC class-I antigens Virus infections present. Primary human embryo kidney cells (HEKs) were grown on 9 cm plastic Petri dishes in Dulbecco's modified Eagle's me-Class-I major histocompatibility complex (MHC) antigens dium (DME) supplemented with 10% FCS. Cells were inare glycoproteins present on the surface of almost all mam-fected with Ad 12 wild-type or mutant viruses at 50 and 200
Proceedings of the National Academy of Sciences, 1986
The adenovirus type 12 (Adl2) early region 1A (EIA) gene is thought to play a major role in repressing class I major histocompatibility complex expression in transformed rodent cells. However, since transformation by adenovirus requires both EIA and EIB genes, it has not been demonstrated whether the Adl2 EIA gene acts alone or synergistically with the EIB gene to accomplish this effect. Moreover, it is not known whether the repression of class I antigen synthesis by Adl2-transforming gene products occurs only in rodent cells. We show that the Adl2 EIA gene, in the absence of the EIB gene, is capable of greatly reducing the levels of class I HLA antigens and mRNAs in primary human cells transformed by the EIA gene of Adl2 and the large tumor antigen (T-antigen) gene of BK virus; control cells transformed by BK virus T-antigen gene alone or the highly related simian virus 40 T-antigen gene showed no apparent alteration in class I HLA expression. Human recombinant interferon y was able to restore synthesis of class I HLA antigens in transformed cells that produced Adl2 ElA proteins, indicating that these cells were not deficient for class I genes. These results strongly indicate that the Adl2 ElA proteins modulate class I gene expression by similar mechanisms in both transformed rodent and human cells.
Proceedings of the National Academy of Sciences, 1987
The E3 19,000-dalton protein termed "E3/ 19K" of adenovirus type 2 binds to human class I histocompatibility antigens (HLA antigens). Human 293.12 cultured cells that express a cloned gene for the E3/19K protein show reduced levels of HLA antigens on the cell surface compared to parental 293 cells. We have transfected these cell lines with plasmid DNA containing the murine histocompatibility H-2Kd allele to demonstrate that this antigen binds also to the E3/19K protein. The resulting association prevents the H-2Kd antigen from being terminally glycosylated and inhibits its cell-surface expression. Two murine cytolytic T-lymphocyte clones specific for HLA antigens and restricted by the H-2Kd antigen lyse the human 293Kd cells. In the presence of the E3/19K protein, a dramatically reduced cell surface density of both HLA and H-2Kd antigens was shown. This decreased amount of cellsurface HLA/H-2Kd antigens correlated with a reduction in susceptibility to lysis of the target cells. In particular, the cell-surface level of the H-2Kd antigen, which is the restricting element, was crucial for efficient lysis. Thus, the E3/19K protein of adenovirus type 2 indirectly reduces the cellular immune recognition in the in vitro system. This might be the mechanism involved in latent and persistent infections caused by adenoviruses in vivo.
Cell, 1977
Six independently isolated adenovirus P-transformed rat cell lines and one adenovirus 54ransformed human cell line have been examined in vitro for serum growth requirements, saturation density, anchorage-independent growth, proteolytic enzyme activity and the presence of LETS glycoprotein and T antigen. This series of adenovirus-transformed cell lines exhibits an oncogenic spectrum ranging from being tumorigenic in immunocompetent rats through to nontumorigenic in adult nude mice. The relevance of the in vitro findings to growth potential in vivo is discussed.
Gene Therapy, 1997
Adenovirus (Ad) vectors are being intensively studied as equally well to treatment and that the response to AdmILvehicles for cancer gene therapy. We have been exploring 12.1 in both groups resulted in the generation of CTL the benefits of direct intratumoral injection of Ads express-reactive against tumor antigen, indicating that antitumor ing cytokines for immunotherapy. Our previous work dem-immunity was achieved. Peak transgene expression in the onstrated that therapy using a vector expressing interleu-tumor was only reduced by 2.4-fold in Ad-immune animals kin-12 (AdmIL-12.1) produced regressions in approxi-compared with nonimmune mice. It was also observed that mately 80% of treated tumors, supporting further preclinical in naive animals, the virus disseminated from the site of the investigations. Recent reports have shown that immunity tumor following injection and by 72 h substantial transgene to Ad can be a major limiting factor in Ad-mediated gene expression was detected in peripheral organs, most transfer. As most animal studies with Ad vectors have notably the liver. Transgene expression in the liver of Adinvolved nonimmune hosts, it remains difficult to predict immune animals was reduced by greater than 1000-fold how effective these treatments will be in humans, where relative to that in naive mice. These results strongly supthe majority of individuals have had previous exposure to port the clinical utility of Ad-based cancer gene therapy and Ad. To address this question, we compared the effective-suggest that Ad immunity may be advantageous in that it ness of the AdmIL-12.1 cancer therapy in naive and Ad-is not a complete block to gene transfer in the tumor and immune mice. We found that both groups responded it greatly reduces virus dissemination.