Research of Epstein-Barr virus-specific T cell immunity targeting the virus-positive cancer

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Epstein-Barr virus (EBV) nuclear antigen (EBNA) 1 is expressed in every EBV-infected cell, regardless of the state of EBV infection. Although EBNA1 is thought to be a promising antigen (Ag) for immunotherapy of all EBV-associated malignancies, it is less clear whether EBNA1-specific CD4^+ T cells can act as direct effectors. Here, we investigated the ability of CD4^+ T cell clones induced with overlapping peptides covering the C-terminal region of EBNA1, and identified minimal epitopes and their restricted MHC class II molecules. Of these, a novel epitope was found to be is presented by DRB1^*0401, 0403, and 0406. Five CD4^+ T cell clones recognized endogenously processed and presented antigens on EBV-transformed lymphoblastoid cell lines and one example proved capable of killing EBV-carrying NK and T cell lines derived from patients with chronic active EBV infection. Identification of minimal epitopes facilitates design of peptide-based vaccines and our data suggest that EBNA1-specific CD4^+ T cells may play roles as direct effectors for immunotherapy targeting EBV-carrying NK and T cell malignancies.