Although adoptive immunotherapy with CD8+ CTL is providing clinically relevant results against EBV-driven malignancies, the effector role of CD4+ T cells has been poorly investigated. We addressed this issue in a lymphoblastoid cell line-induced mouse model of posttransplant lymphoproliferative disease (PTLD) by comparing the therapeutic efficacy of EBV-specific CD4+ and CD8+ T cell lines upon adoptive transfer. CD4+ T cells disclosed a long-lasting and stronger proliferative potential than CD8+ T cells, had a similar activation and differentiation marker profile, efficiently killed their targets in a MHC class II-restricted manner, and displayed a lytic machinery comparable to that of cognate CD8+ T cells. A detailed analysis of Ag specificity revealed that CD4+ T cells potentially target EBV early lytic cycle proteins. Nonetheless, when assessed for the relative therapeutic impact after in vivo transfer, CD4+ T cells showed a reduced activity compared with the CD8+ CTL counterpart. This feature was apparently due to a strong and selective downmodulation of MHC class II expression on the tumor cells surface, a phenomenon that could be reverted by the demethylating agent 5-aza-2′-deoxycytidine, thus leading to restoration of lymphoblastoid cell line recognition and killing by CD4+ T cells, as well as to a more pronounced therapeutic activity. Conversely, immunohistochemical analysis disclosed that HLA-II expression is fully retained in human PTLD samples. Our data indicate that EBV-specific cytotoxic CD4+ T cells are therapeutic in mice bearing PTLD-like tumors, even in the absence of CD8 + T cells. These findings pave the way to use cultures of pure CD4+ T cells in immunotherapeutic approaches for EBV-related malignancies.
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