CD4+ T cell responses in the immune control against latent infection by Epstein-Barr virus

The human gamma-herpesvirus Epstein-Barr virus establishes latent, life-long infection in more than 95% of the human adult population. Despite its growth transforming capacity, most carriers control EBV associated malignancies efficiently and remain free of EBV+ tumors. It is commonly accepted that lymphoblastoid cells, expressing all EBV latent antigens, are targeted by the immune system and cause tumors only in immune-suppressed individuals. However, immune control of EBV associated malignancies which express only three or one EBV latent antigen is less obvious. Recent studies have addressed the pattern of EBV latent infection in healthy EBV carriers and the identity of EBV derived target antigens for CD4+ T cells. The results suggest that immune surveillance also extends to tumors, which have down-regulated most EBV latent antigens and therefore escape EBV specific immune recognition at least in part. EBV specific immunity that targets these tumors in healthy EBV carriers seems to fail specifically during the development of Hodgkin's disease, nasopharyngeal carcinoma and Burkitt's lymphoma. These three EBV+ tumors appear to subdue EBV immunity against the remaining EBV latent antigens in different ways or profit from the effect of other pathogens on EBV specific immune responses, when they develop in otherwise immune competent individuals. While immune control and immune escape of these so-called spontaneously arising EBV associated malignancies is just beginning to be understood, immune control of persisting EBV infection can serve as a model for tumor immune surveillance in general.