aberrant expression of HLA Class‐I antigens in burkitt lymphoma cells

Abstract

HLA class-I expression has been investigated by biochemical methods in 14 Burkitt lymphoma (BL) cell lines and the corresponding Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCL) derived from the same individuals. Selective down-regulation of one or more HLA class-I specificities was demonstrated in 9 out of 14 BL lines. The defect was restricted to a single HLA-A allele in 3 of the lines (BL29, BL72, WW-I-BL). Four lines (BL28, BL37, BL41 and Jijoye M13) showed down-regulation of both HLA-A and -C alleles, and one (BL36) failed to express one HLA-C allele. Only one BL line (WW-2-BL) had lost one HLA-A and one HLA-B allele. The allele-specific defects were mainly detected in cell lines that had maintained the phenotypic characteristics of the original tumor. Expression of B-cell activation markers and the EBV-encoded nuclear antigen (EBNA)-2 correlated with up-regulation of the Cw4 allele in the P79 subline of the BL line Jijoye. Treatment with gamma-interferon (IFN) resulted in full or partial reversion of the HLA class-I defects in some of the cases but had no significant effect in others. This was not due to a cell-line-related unresponsiveness to IFN, nor did it reflect an allele-specific mode of regulation because the same allele could respond differently in different cell lines. The data suggest that defective expression of HLA class-I antigens, which appears to be more prevalent for alleles within the HLA-A and -C loci, is a common feature of BL cell lines. Different regulatory mechanisms appear to be involved.

Recognition of the Epstein-Barr virus-encoded nuclear antigens EBNA-4 and EBNA-6 by HLA-A11-restricted cytotoxic T lymphocytes: implications for down-regulation of HLA-A11 in Burkitt lymphoma.

“…It is noteworthy that allele-selective defects of HLA class I were detected in phenotypically representative cell lines derived from both EBV-carrying and EBV-negative tumors (15). There are two possible interpretations for this finding.…”

“…We have indeed shown that germinal center centroblasts express significantly lower levels of HLA class I compared to B blasts and memory B cells (18). This explanation, however, does not account for the heterogeneity of the HLA class I defects in BLs and the different capacity to restore allele-selective defects after interferon treatment (15). It is also inconsistent with the observation that HLA-A11 expression can be restored by transfection of plasmids carrying the gene under control of the autologous promoter (M.G.M., unpublished data).…”

“…The phenotypic differences between LCL and BL cells are consistent with this possibility. BL biopsies and representative cell lines express only EBNA-1 (12), have relatively low expression of adhesion molecules (13) and HLA class I (14), and show a selective down-regulation of certain HLA-A and -C alleles (15). The most common HLA class I defect recorded in BL lines is a selective down-regulation of HLA-A11, which has been found to occur in all seven BL lines derived from HLA-A11-positive individuals investigated so far (ref.…”

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

“…In all cases, the viral EBNA-2 and LMP-1 are not expressed and, as a result, EBV-positive BL cells do not express B-cell activation markers, adhesion and costimulatory molecules and grow as single cell suspensions rather than in clumps (Rowe et al, 1986). Characteristic for the tumor cells are also the low levels of MHC class I and selective loss of certain class I alleles, HLA A11 in particular (Andersson et al, 1991), which may contribute to the poor allostimulatory capacity of these cells in mixed lymphocyte cultures (Avila-Carino et al, 1987). In addition, BL cells are deficient in their ability to present endogenous antigens via the MHC class I pathway (Frisan et al, 1996), which correlates with downregulation of the interferon-ginducible subunits of the proteasome and the peptide transporters TAP1 and TAP2 Frisan et al, 1998).…”

Analysis of MHC class I and II expression in relation to presence of HPV genotypes in premalignant and malignant cervical lesions

“…In these samples both normal and altered MHC-I and -II expression could be detected. (Andersson et al, 1991), small cell lung cancer (Doyle et' al., 1985), breast cancer (Fleming et al, 1981) and melanomas (Brocker et al, 1985). Also in cervical carcinomas this phenomenon has been observed in a substantial number of the carcinomas examined (Connor & Stern, 1990).…”