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Epstein–Barr virus nuclear antigen 1‐specific CD4+ T cells directly kill Epstein–Barr virus‐carrying natural killer and T cells

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 for immunotherapy of all EBV‐associated malignancies, it is less clear whether EBNA1‐specific CD4+ T cells can act as direct effectors. Herein, 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 major histocompatibility complex class II molecules. Of these, a novel epitope, EYHQEGGPD, was found to be presented by DRB1*0401, 0403 and 0406. Five CD4+ T‐cell clones recognized endogenously processed and presented antigens on EBV‐transformed lymphoblastoid cell lines (LCL) and one example proved capable of killing EBV‐carrying natural killer (NK) and T‐cell lines derived from patients with chronic active EBV infection (CAEBV). 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. (Cancer Sci 2008; 99: 1633–1642)