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

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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.