Induction of EBV-latent membrane protein 1-specific MHC class II-restricted T-cell responses against natural killer lymphoma cells
Induction of EBV-latent membrane protein 1-specific MHC class II-restricted T-cell responses against natural killer lymphoma cells
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DOI：
10.1158/0008-5472.can-07-3212
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发表时间：
2008-02-01
期刊：
影响因子：
11.2
通讯作者：
Celis, Esteban
中科院分区：
文献类型：
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作者：
Kobayashi, Hiroya;Nagato, Toshihiro;Celis, Esteban
ebv编码的潜伏膜蛋白1 （LMP1）具有致癌潜能，并在许多ebv相关的恶性肿瘤中表达。尽管LMP1被认为是免疫治疗的潜在肿瘤相关抗原，并且已经报道了几种LMP1特异性MHC i类限制性CTL表位，但对LMP1的MHC ii类限制性CD4辅助t淋巴细胞（HTL）表位知之甚少。本研究的目的是确定MHC ii类限制性CD4 t细胞反应是否可以诱导对抗LMP1抗原，并评估这些反应的抗肿瘤作用。我们将预测MHC II类结合肽算法与使用候选肽的CD4 T细胞体外疫苗接种相结合，以鉴定来自LMP1的自然加工表位，这些表位可引发针对表达ebv的肿瘤细胞的免疫应答。肽IMP1（159-175）可有效诱导受HLA-DR9、HLA-DR53或HLA-DR15限制的HTL反应，这表明该肽的行为是一个混杂的t细胞表位。此外，LMP1(159-175)-反应性HTL克隆直接识别EBV淋巴母细胞样B细胞，EBV感染的自然杀伤(NK)/ t淋巴瘤细胞和自然处理抗原，以LMP1+肿瘤细胞裂解物的形式由自体树突状细胞呈递。由于新发现的表位LMP1（159-175）与hla - a2限制性CTL表位LMP1（159-167）重叠，该肽可能具有诱导LMP1同时发生CTL和HTL应答的能力。总的来说，我们的数据应该与设计和优化基于T细胞表位的免疫疗法有关，用于治疗各种ebv相关的恶性肿瘤，包括NK/T细胞淋巴瘤。
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 IMP1(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.