title: Identification and characterization of a WT1 (Wilms Tumor Gene) protein-derived HLA-DRB1*0405-restricted 16-mer helper peptide that promotes the induction and activation of WT1-specific cytotoxic T lymphocytes.
abstract: Effective tumor vaccine may be required to induce both cytotoxic T lymphocyte (CTL) and CD4+ helper T-cell responses against tumor-associated antigens. CD4+ helper T cells that recognize HLA class II-restricted epitopes play a central role in the initiation and maintenance of antitumor immune responses. The Wilms tumor gene WT1 is overexpressed in both leukemias and solid tumors, and the WT1 protein was demonstrated to be an attractive target antigen for cancer immunotherapy. In this study, we identified a WT1 protein-derived 16-mer peptide, WT1(332)(KRYFKLSHLQMHSRKH), which was restricted with HLA-DRB1*0405, one of the most common HLA class II types in Japanese, as a helper epitope that could elicit WT1-specific CD4+ T-cell responses. We established a WT1(332)-specific CD4+ helper T-cell clone (E04.1), which could respond to both HLA-DRB1*0405-positive, WT1-expressing transformed hematopoietic cells and autologous dendritic cells pulsed with apoptosis-induced WT1-expressing cells, indicating that the WT1(332) was a naturally processed helper epitope. Stimulation of peripheral blood mononuclear cells with both the CTL epitope (WT1(235)) and the helper epitope (WT1(332)) in the presence of WT1(332)-specific TH1-type CD4+ T cell clone strikingly enhanced the induction and the functional activity of WT1(235)-specific CTLs compared with that of peripheral blood mononuclear cells with the WT1(235) alone. These results indicated that a helper epitope, WT1(332) should be useful for improvement of the efficacy of CTL epitope-based cancer vaccine targeting WT1 in the clinical setting.
authors.affiliation: Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Fujiki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Oka
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tsuboi
authors.forename: Manabu
authors.initials: M
authors.lastname: Kawakami
authors.forename: Mai
authors.initials: M
authors.lastname: Kawakatsu
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakajima
authors.forename: Olga A
authors.initials: OA
authors.lastname: Elisseeva
authors.forename: Yukie
authors.initials: Y
authors.lastname: Harada
authors.forename: Ken
authors.initials: K
authors.lastname: Ito
authors.forename: Zheyu
authors.initials: Z
authors.lastname: Li
authors.forename: Naoya
authors.initials: N
authors.lastname: Tatsumi
authors.forename: Nao
authors.initials: N
authors.lastname: Sakaguchi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Fujioka
authors.forename: Tomoki
authors.initials: T
authors.lastname: Masuda
authors.forename: Masaki
authors.initials: M
authors.lastname: Yasukawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Udaka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Oji
authors.forename: Haruo
authors.initials: H
authors.lastname: Sugiyama
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D016162:Genes, Wilms Tumor; D006684:HLA-DR Antigens / Q000276:immunology*; D059811:HLA-DRB1 Chains; D006801:Humans; D007371:Interferon-gamma; D008213:Lymphocyte Activation; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D025721:WT1 Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C493960:HLA-DRB1*04:05 antigen; D009842:Oligopeptides; D025721:WT1 Proteins; C520525:WT1(332)(KRYFKLSHLQMHSRKH); D007371:Interferon-gamma