Down-regulation of class I HLA antigens and of the Epstein-Barr virus-encoded latent membrane protein in Burkitt lymphoma lines.

Abstract

Epstein-Barr virus (EBV)-carrying Burkitt lymphoma (BL) cells are relatively or completely resistant to the lytic effect of major histocompatibility complex class I HLA antigen-restricted cytotoxic T lymphocytes (CTLs) generated by stimulating lymphocytes of EBV-seropositive donors with the autologous EBV-transformed lymphoblastoid cell line (LCL). We previously found that EBV-negative and EBVcarrying BL lines derived from HLA-All-positive donors were not only resistant to lysis by the HLA-All-restricted CTL generated by stimulation with the autologous LCL, but also to HLA-All-specific CTL derived from lymphocytes of an EBVseronegative donor stimulated with an allogeneic LCL. Using the same and additional cell lines, we now show that the CTL resistance of the BL lines is probably due to a selective down-regulation of HLA-All. We also show that the EBVencoded latent membrane protein is expressed at a lower level in the EBV-carrying BL lines than in EBV-transformed LCLs. Only one of eight in vitro EBV-converted BL lines that shifted to a more LCL-like growth pattern expressed LMP at a high level. This line also reexpressed the HLA-All antigen that was undetectable in its EBV-negative progenitor. Our rmdings suggest that the typical BL cell phenotype is associated with low expression of both proteins.Reciprocal translocations juxtapose the cellular c-myc gene (MYC gene in humans) to an immunoglobulin locus in Epstein-Barr virus (EBV)-carrying and EBV-negative Burkitt lymphoma (BL) lines and in mouse and rat plasmacytomas (1, 2). It has been suggested that the translocations contribute to the tumorigenic process by bringing the c-myc gene under the regulatory influence of the adjacent, highly active immunoglobulin locus. This concept is supported by the high incidence of pre-B-cell and B-cell lymphomas in transgenic mice that carried immunoglobulin heavy chain Igh enhancer-myc constructs (3) and the appearance of translocation-free plasmacytomas in pristane oil-treated BALB/c mice infected with myc-expressing retroviral constructs (4). However, the monoclonality of the B-cell tumors that arose in the transgenic mice carrying the Igh enhancer-myc construct indicates that at least one additional step is needed for full tumorigenicity.EBV-carrying BL cells are relatively or completely resistant to the lytic effect of major histocompatibility complex (MHC) class I HLA antigen-restricted cytotoxic T lymphomas (CTLs) generated by stimulating lymphocytes of EBVseropositive donors with the autologous EBV-transformed lymphoblastoid cell line (LCL) (5,6). This was taken to suggest that escape from immune surveillance may play a role in the pathogenesis of the EBV-positive BL lines.We have found that EBV-negative and EBV-carrying BL lines derived from HLA-A1l-positive donors were not only resistant to lysis by the HLA-All-restricted CTLs generated by stimulation with the autologous LCL but also the HLAAll-specific CTLs generated by stimulating the lymphocytes of an EBV-seronegative donor with an allogeneic LCL (6). We ...

HLA class I gene expression on human primary tumours and autologous metastases: demonstration of selective losses of HLA antigens on colorectal, gastric and laryngeal carcinomas

“…These losses of K or D molecules were correlated with an enhanced metastatic ability (Eisenbach et al, 1983). It has recently been reported that the resistance of certain Burkitt lymphomas to lysis by autologous cytotoxic T-lymphocytes may be due to the selective loss of HLA-A1 1 antigen expression (Masucci et al, 1988). Selective losses of HLA-B locus products have been recently reported in colorectal carcinomas (Garrido, 1988;Smith et al, 1988).…”

Loss of monomorphic and polymorphic HLA antigens in metastatic breast and colon carcinoma

“…Failure to express HLA class I, or the expression of inappropriate or altered HLA components on cells, is a possible mechanism whereby tumour cells may escape destruction by antigen specific CTL. Several studies have now shown that many human tumours fail to express antigens recognised by monoclonal antibodies (mAbs) specific for the monomorphic sites of HLA class I molecules (Masucci et al, 1987;Smith et al, 1988;Broker et al, 1984;Lopez-Nevot et al, 1989;Momburg et al, 1986;Momburg & Koch, 1989;Muller & Stutte, 1988;Natali et al, 1983;Perez et al, 1986). Furthermore, some primary human colon carcinomas fail to express HLA class I polymorphic regions (Rees et al, 1988;Momburg & Koch, 1989); the absence of these haplotypes may also be significant.…”

Presentation of CMV immediate-early antigen to cytolytic T lymphocytes is selectively prevented by viral genes expressed in the early phase

“…Because of its selectivity, the inhibition of pp89 presentation is unlike other reported cases of interference with antigen recognition by CTLs, all of which could be explained by a general decrease in the surface levels of ce 1-lular presenting or adhesion moleeules (Gooding, 1982;Bernards et al , 1983;Jennings et al, 1985;Masucci et al , 1987;Gregory et al. 1988) that indiscriminately affects the presentation of any antigen.…”

“…membrane proteins required for the recognition of infected ceUs by cytolytic T Iymphocytes (CTLs). For several viruses (Gooding, 1982;Bernards et al, 1983), including herpesviruses (Jennings et al , 1985;Masucci et al , 1987), defective antigen recognition has been associated with decreased surface levels of MHC class I glycoproteins. For adenoviruses, there is evidence that the underlying mechanism is an active interference with class I mRNA processing (Vaessen et al, 1987) or with glycosylation (Burgert and Kvist.…”