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.
Highlights
Epstein-Barr virus (EBV) infection can be found in lymphoid malignancies of B-cell lineage, and of T- or NK-cell lineages
These EBV-positive T or NK-cell neoplasms, such as extranodal NK/T-cell lymphoma nasal type (ENKL), aggressive NK-cell leukemia (ANKL), and EBV-positive T- or NK- cell lymphoproliferative diseases (EBV-T/NK-LPDs), are relatively rare but lethal disorders classified as peripheral T/NK-cell lymphomas according to the WHO classification of tumors of hematopoietic and lymphoid malignancies
To clarify the molecular mechanism underlying the development of EBV-T/NK-neoplasms, we focused on the costimulatory receptor CD137
Summary
Epstein-Barr virus (EBV) infection can be found in lymphoid malignancies of B-cell lineage, and of T- or NK-cell lineages These EBV-positive T or NK-cell neoplasms, such as extranodal NK/T-cell lymphoma nasal type (ENKL), aggressive NK-cell leukemia (ANKL), and EBV-positive T- or NK- cell lymphoproliferative diseases (EBV-T/NK-LPDs), are relatively rare but lethal disorders classified as peripheral T/NK-cell lymphomas according to the WHO classification of tumors of hematopoietic and lymphoid malignancies. The common clinical properties of EBV-T/NKneoplasms are the presence of severe inflammation, resistance to chemotherapy, and a marked geographic bias for East Asia and Latin America, suggesting a genetic context for disease development [4]. Since these EBV-T/NK-neoplasms overlap [4], common mechanisms are thought to exist in the background and contribute to disease development
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