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
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
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DOI：
10.1097/01.cji.0000211337.91513.94
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发表时间：
2007-04-01
影响因子：
3.9
通讯作者：
Sugiyama, Haruo
中科院分区：
文献类型：
--
作者：
Fujiki, Fumihiro;Oka, Yoshihiro;Sugiyama, Haruo
有效的肿瘤疫苗可能需要诱导针对肿瘤相关抗原的细胞毒性T淋巴细胞（CTL）和CD 4（+）辅助性T细胞应答。识别HLA II类限制性表位的CD 4（+）辅助性T细胞在抗肿瘤免疫应答的启动和维持中发挥核心作用。Wilms肿瘤基因WT 1在白血病和实体瘤中过表达，并且WT 1蛋白被证明是癌症免疫治疗的有吸引力的靶抗原。在这项研究中，我们鉴定了WT 1蛋白衍生的16-mer肽，WT 1（332）（KRYFKLSHLQMHSRKH），其被HLA-DRB 1 *0405限制，HLA-DRB 1 *0405是日本人最常见的HLA 11型之一，作为辅助表位，可以引发WT 1特异性CD 4（+）T细胞应答。我们建立了WT 1（332）特异性CD 4+辅助T细胞克隆（E04.1），其可以对HLA-DR 131 *0405阳性的、表达WT 1的转化造血细胞和自体树突状细胞（其用骨髓增生诱导的表达WT 1的细胞脉冲）应答，表明WT 1（332）是天然加工的辅助表位。与仅用WT 1235的外周血单核细胞相比，在WT 1332特异性TH 1型CD 4（+）T细胞克隆存在下，用CTL表位（WT 1（235））和辅助表位（WT 1332）刺激外周血单核细胞显著增强了WT 1（235）特异性CTL的诱导和功能活性。这些结果表明，辅助表位，WT 1332应该是有用的，以提高CTL表位为基础的癌症疫苗靶向WT 1在临床上的效果。
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 11 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-DR131*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 (WT1332) in the presence of WT1332-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 WT1235 alone. These results indicated that a helper epitope, WT1332 should be useful for dimprovement of the efficacy of CTL epitope-based cancer vaccine targeting WT1 in the clinical setting.