Epstein-Barr virus (EBV) latent membrane protein-1-specific cytotoxic T lymphocytes targeting EBV-carrying natural killer cell malignancies.
Epstein-Barr virus (EBV)-encoded latent membrane protein (LMP) 1 is a potential target for immunotherapy of some proportion of Hodgkin's disease cases, nasopharyngeal carcinomas, EBV-associated natural killer (NK)/T lymphomas, and chronic active EBV infection (CAEBV). Since it is unknown whether EBV-infected NK/T cells are susceptible to lysis by LMP1-specific cytotoxic T lymphohcytes (CTL), we here tested the ability of mRNA-transduced antigen-presenting cells (APC) to stimulate rare LMP1-specific CTL. A 43-amino acid N-terminal deletion mutant LMP1 (DeltaLMP1) could be efficiently expressed in dendritic cells and CD40-activated B cells upon mRNA electroporation. DeltaLMP1-expressing APC were found to stimulate LMP1-specific CTL from a healthy donor and a CTL clone recognized a peptide, IIIILIIFI, presented by HLA-A*0206 molecules. Processing and presentation of the antigenic peptide proved dependent on expression of an immunoproteasome subunit, low-molecular-weight protein-7, as confirmed by RNA interference gene silencing. Furthermore, an EBV-infected NK cell line derived from a patient with CAEBV, and another from an NK lymphoma with enforced HLA-A*0206 expression, were specifically lysed by the CTL. Overall, these data suggest that immunotherapy targeting LMP1 in EBV-associated NK lymphomas and CAEBV might serve as an alternative treatment modality.
Division of Immunology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Ayako
A
Demachi-Okamura
Yoshinori
Y
Ito
Yoshiki
Y
Akatsuka
Kunio
K
Tsujimura
Yasuo
Y
Morishima
Toshitada
T
Takahashi
Kiyotaka
K
Kuzushima
D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002277:Carcinoma / Q000276:immunology / Q000628:therapy / Q000821:virology; D045744:Cell Line, Tumor; D002908:Chronic Disease; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015870:Gene Expression; D015234:HLA-A Antigens / Q000276:immunology; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy / Q000821:virology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D008213:Lymphocyte Activation / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy / Q000821:virology; D009303:Nasopharyngeal Neoplasms / Q000276:immunology / Q000628:therapy / Q000821:virology; D010455:Peptides / Q000235:genetics / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D034622:RNA Interference / Q000276:immunology; D012333:RNA, Messenger / Q000276:immunology; D017384:Sequence Deletion / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014162:Transfection / Q000379:methods; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*
D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D015234:HLA-A Antigens; D010455:Peptides; D012333:RNA, Messenger; D014763:Viral Matrix Proteins; D046988:Proteasome Endopeptidase Complex