title: Induction of EBV-latent membrane protein 1-specific MHC class II-restricted T-cell responses against natural killer lymphoma cells.
abstract: EBV-encoded latent membrane protein 1 (LMP1) has oncogenic potential and is expressed in many EBV-associated malignancies. Although LMP1 is regarded as a potential tumor-associated antigen for immunotherapy and several LMP1-specific MHC class I-restricted CTL epitopes have been reported, little is known regarding MHC class II-restricted CD4 helper T-lymphocyte (HTL) epitopes for LMP1. The goal of the present studies was to determine whether MHC class II-restricted CD4 T-cell responses could be induced against the LMP1 antigen and to evaluate the antitumor effect of these responses. We have combined the use of a predictive MHC class II binding peptide algorithm with in vitro vaccination of CD4 T cells using candidate peptides to identify naturally processed epitopes derived from LMP1 that elicit immune responses against EBV-expressing tumor cells. Peptide LMP1(159-175) was effective in inducing HTL responses that were restricted by HLA-DR9, HLA-DR53, or HLA-DR15, indicating that this peptide behaves as a promiscuous T-cell epitope. Moreover, LMP1(159-175)-reactive HTL clones directly recognized EBV lymphoblastoid B cells, EBV-infected natural killer (NK)/T-lymphoma cells and naturally processed antigen in the form of LMP1+ tumor cell lysates presented by autologous dendritic cells. Because the newly identified epitope LMP1(159-175) overlaps with an HLA-A2-restricted CTL epitope (LMP1(159-167)), this peptide might have the ability to induce simultaneous CTL and HTL responses against LMP1. Overall, our data should be relevant for the design and optimization of T-cell epitope-based immunotherapy against various EBV-associated malignancies, including NK/T cell lymphomas.
authors.affiliation: Department of Pathology, Asahikawa Medical College, Asahikawa, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nagato
authors.forename: Miki
authors.initials: M
authors.lastname: Takahara
authors.forename: Keisuke
authors.initials: K
authors.lastname: Sato
authors.forename: Shoji
authors.initials: S
authors.lastname: Kimura
authors.forename: Naoko
authors.initials: N
authors.lastname: Aoki
authors.forename: Makoto
authors.initials: M
authors.lastname: Azumi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Tateno
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D002051:Burkitt Lymphoma / Q000276:immunology*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D016399:Lymphoma, T-Cell / Q000276:immunology*; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D010446:Peptide Fragments; D014763:Viral Matrix Proteins