CD137 Expression Is Induced by Epstein-Barr Virus Infection through LMP1 in T or NK Cells and Mediates Survival Promoting Signals

Abstract

To clarify the mechanism for development of Epstein-Barr virus (EBV)-positive T- or NK-cell neoplasms, we focused on the costimulatory receptor CD137. We detected high expression of CD137 gene and its protein on EBV-positive T- or NK-cell lines as compared with EBV-negative cell lines. EBV-positive cells from EBV-positive T- or NK-cell lymphoproliferative disorders (EBV-T/NK-LPDs) patients also had significantly higher CD137 gene expression than control cells from healthy donors. In the presence of IL-2, whose concentration in the serum of EBV-T/NK-LPDs was higher than that of healthy donors, CD137 protein expression was upregulated in the patients' cells whereas not in control cells from healthy donors. In vitro EBV infection of MOLT4 cells resulted in induction of endogenous CD137 expression. Transient expression of LMP1, which was enhanced by IL-2 in EBV-T/NK-LPDs cells, induced endogenous CD137 gene expression in T and NK-cell lines. In order to examine in vivo CD137 expression, we used EBV-T/NK-LPDs xenograft models generated by intravenous injection of patients' cells. We identified EBV-positive and CD8-positive T cells, as well as CD137 ligand-positive cells, in their tissue lesions. In addition, we detected CD137 expression on the EBV infected cells from the lesions of the models by immune-fluorescent staining. Finally, CD137 stimulation suppressed etoposide-induced cell death not only in the EBV-positive T- or NK-cell lines, but also in the patients' cells. These results indicate that upregulation of CD137 expression through LMP1 by EBV promotes cell survival in T or NK cells leading to development of EBV-positive T/NK-cell neoplasms.

EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells

“…We previously reported that EBV infection induced ectopic but endogenous CD40 expression n T and NK cells thereby promoting their survival in an autocrine manner via a CD40 ligand, CD154, which was initially expressed on the surface of EBV-T/NK cells [19, 30]. In addition, we reported that EBV infection induced CD137 expression on the surface of T cells, which subsequently mediated anti-apoptotic signals [20]. Because NF-κB can be activated downstream of CD40 and CD137 [31, 32], EBV-induced CD40 or CD137 expression may play a role in NF-κB activation in EBV-T/NK cells.…”

“…MOLT4 or MOLT4-DL cells were infected with EBV as described previously [19, 20]. Briefly, spontaneously produced EBV was prepared from the culture medium of B95-8 cells.…”

“…RT-PCR for the detection of mRNA encoding the viral proteins LMP1, LMP2A, LMP2B, and EBNA1 was performed according to previous reports [20, 22]. …”

Successful Treatment of Genetically Profiled Pediatric Extranodal NK/T‐Cell Lymphoma Targeting Oncogenic STAT3 Mutation

“…A definitive histological diagnosis requires the identification of atypical hematopoietic cells on a background of inflammatory, necrotic, and degenerating cells . Furthermore, ENKTCL is strongly linked to EBV, suggesting an important oncogenic role of the virus . The exceedingly rare clinical presentation of this case warranted the combined use of both immunophenotyping and genomic profiling to arrive at an accurate diagnosis.…”

“…[1,6] Furthermore, ENKTCL is strongly linked to EBV, suggesting an important oncogenic role of the virus. [13,14] The exceedingly rare clinical presentation of this case warranted the combined use of both immunophenotyping and genomic profiling to arrive at an accurate diagnosis.…”