Identification of T-helper peptide-epitopes against gene product of Epstein-Barr virus and Hunan T-cell leukemia virus type I.

EB病毒（EBV）编码的潜伏膜蛋白1（LMP 1）具有致癌潜力，并在许多EBV相关的恶性肿瘤中表达。虽然LMP 1被认为是一种潜在的肿瘤相关抗原（TAA）的免疫治疗和几个LMP 1特异性的MHC I类限制性CTL表位已被报道，很少有人知道关于MHC II类限制性CD 4辅助T淋巴细胞（HTL）表位LMP 1。本研究的目的是确定是否可以针对LMP 1抗原诱导MHC II类限制性CD 4 T细胞应答，并评估这些应答的抗肿瘤作用。我们已经将预测性MHC II类结合肽算法的使用与使用候选肽的CD 4 T细胞的体外疫苗接种相结合，以鉴定衍生自LMP 1的天然加工表位，所述表位引发针对表达EBV的肿瘤细胞的免疫应答。肽LMP 1有效<159-175>诱导受HLA-DR 9、DR 53或DR 15限制的HTL应答，表明该肽表现为混杂的T细胞表位。此外，LMP 1-<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NK/T淋巴瘤细胞和以自体树突状细胞呈递的LMP 1+肿瘤细胞裂解物形式的天然加工抗原。由于新鉴定的表位LMP 1_<159-175>与HLA-A2限制性CTL表位（LMP 1_）重叠<159-175>，因此该肽可能具有诱导针对LMP 1的同时CTL和HTL应答的能力。总的来说，我们的数据应该是相关的设计和优化的T细胞表位为基础的免疫治疗对各种EBV相关的恶性肿瘤，包括NK/T细胞淋巴瘤。

Epstein-Barr virus (EBV)-encoded latent membrane protein l (LMP1) has oncogenic potential and is expressed in many EBV-associated malignancies. Although LMP1 is regarded as a potential tumor associated antigen (TAA) 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 lymphocytes (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 anti-tumor 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, DR53 or 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 NK/T lymphoma cells and naturally processed antigen in the form of LMP1+ tumor-cell lysates presented by autologous dendritic cells. Since the newly identified epitope LMP1_<159-175> overlaps with an HLA-A2-restricted CTL epitope (LMP1_<159-175>), this peptide might have ability of inducing 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.