Abstract
BACKGROUND: In chronic active Epstein-Barr virus (EBV) (CAEBV) disease, EBV infects T or natural killer (NK) cells, and patients frequently exhibit a broad spectrum of EBV-associated T/NK-cell lymphoproliferative disorders including polyclonal, oligoclonal, and monoclonal proliferation, and sometimes develop EBV-positive NK/T-cell lymphoma. In the development of malignant tumor, the acquisition of the ability of resisting cell death is an important factor. METHODS: We have introduced a plasmid containing the coding sequences of EBV-encoded small RNAs (EBERs) or latent membrane protein (LMP) 1 into human T-lymphocyte virus-I-negative human T-cell lines using an expression plasmid vector harboring EBV nuclear antigen 1 and established stable transformants. Using these stable transformants, we evaluated the change of sensitivity to apoptosis induction with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L or soluble FasL (sFasL) in T cell lines with the expression of latent EBV genes, EBERs or LMP1. RESULTS: Among five human T-cell lines examined, Jurkat was the most sensitive cell line to the induction of cell death with both of Apo2L and sFasL, and the stable transformants of Jurkat cells expressing EBERs (Jurkat/E6) or LMP1 (Jurkat/L) exhibited the resistance to the cell death induced with both of Apo2L and sFasL. In Jurkat/E6 cells, the expression of cFLIP(S), which blocks procaspase-8 activation and apoptosis, was a little enhanced, and in Jurkat/L cells, the phosphorylation of IκBα was constitutively upregulated, which leads to cell survival signals. Furthermore, Jurkat/E6 cells with decrease expression of EBERs after 6-months-culture without plasmid selection antibiotics exhibited the restored sensitivity to both death ligands-induced apoptosis in part, although Jurkat/L cells with decreased expression of LMP1 did not. CONCLUSION: EBERs would be responsible for the induction of resistance to death-ligand-induced apoptosis, and might contribute to the development of EBV-positive lymphoma of non-B-cell lineage. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13027-026-00736-9.