Defining MHC class II T helper epitopes for WT1 tumor antigen
Defining MHC class II T helper epitopes for WT1 tumor antigen
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DOI：
10.1007/s00262-005-0071-0
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发表时间：
2006-07-01
影响因子：
5.8
通讯作者：
Celis, E
中科院分区：
文献类型：
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作者：
Kobayashi, H;Nagato, T;Celis, E
Wilms的肿瘤基因1(WT1)的产物在包括白血病、肺癌和乳腺癌在内的多种人类肿瘤中过表达，并经常被白血病患者血清中的抗体识别。由于WT1编码细胞毒性T淋巴细胞(CTL)识别的MHC-I类限制性多肽，WT1被认为是一种很有前途的肿瘤相关抗原(TAA)，可用于抗癌免疫治疗。为了进行有效的基于多肽的肿瘤免疫治疗，需要MHC-II类限制性表位多肽来诱导抗肿瘤的CD4+STOP辅助T淋巴细胞(HTL)。在这项研究中，我们使用体外免疫人淋巴细胞的HTL株来分析HTL对WT1抗原的反应，合成的多肽被预测为来自WT1序列的HTL表位。WT1(124 138)和WT1(247 261)两个多肽可诱导多肽特异性HTL，且受频繁表达的HLAII类等位基因的限制。在这里，我们还证明了两个多肽反应性HTL株都能够识别由肿瘤裂解物冲击的树突状细胞或直接由表达MHC II类分子的WT1+肿瘤细胞呈递的自然处理的抗原。有趣的是，这里描述的两个WT1 HTL表位与已知的MHC I类限制性CTL表位非常接近，这增加了使用相对较小的合成肽疫苗刺激CTL和HTL反应的可能性。由于已知HTL对TAA的应答对于促进持久的抗肿瘤CTL应答是重要的，新描述的WT1T辅助表位可能为设计针对WT1表达的肿瘤的强大疫苗提供有用的工具。
The product of Wilms' tumor gene 1 (WT1) is overexpressed in diverse human tumors, including leukemia, lung and breast cancer, and is often recognized by antibodies in the sera of patients with leukemia. Since WT1 encodes MHC class I-restricted peptides recognized by cytotoxic T lymphocytes (CTL), WT1 has been considered as a promising tumor-associated antigen (TAA) for developing anticancer immunotherapy. In order to carry out an effective peptide-based cancer immunotherapy, MHC class II-restricted epitope peptides that elicit anti-tumor CD4+ stop helper T lymphocytes (HTL) will be needed. In this study, we analyzed HTL responses against WT1 antigen using HTL lines elicited by in vitro immunization of human lymphocytes with synthetic peptides predicted to serve as HTL epitopes derived from the sequence of WT1. Two peptides, WT1(124 138) and WT1(247 261), were shown to induce peptide-specific HTL, which were restricted by frequently expressed HLA class II alleles. Here, we also demonstrate that both peptides-reactive HTL lines were capable of recognizing naturally processed antigens presented by dendritic cells pulsed with tumor lysates or directly by WT1+ tumor cells that express MHC class II molecules. Interestingly, the two WT1 HTL epitopes described here are closely situated to known MHC class I-restricted CTL epitopes, raising the possibility of stimulating CTL and HTL responses using a relatively small synthetic peptide vaccine. Because HTL responses to TAA are known to be important for promoting long-lasting anti-tumor CTL responses, the newly described WT1 T-helper epitopes could provide a useful tool for designing powerful vaccines against WT1-expressing tumors.