title: 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.
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yoshimori
authors.affiliation: Department of Infectious Diseases, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Imadome
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Honami
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ludan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Molecular Virology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Saitoh
authors.affiliation: Department of Molecular Virology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Department of Comprehensive Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Morito
authors.initials: M
authors.lastname: Kurata
authors.affiliation: Department of Laboratory Molecular Genetics of Hematology, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Koyama
authors.affiliation: Department of Virology, Division of Medical Science, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Infectious Diseases, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Fujiwara
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Miura
authors.affiliation: Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Arai
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*; D055815:Young Adult
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D007376:Interleukin-2; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014763:Viral Matrix Proteins