Dendritic Cells for the Induction of EBV Immunity

Abstract

Cell-mediated immunity provides resistance to Epstein-Barr virus (EBV), as demonstrated by the occurrence of EBV-induced post-transplant lymphoproliferative disease (PTLPD) in immunosuppressed patients. T cell immunity is stimulated most effectively by dendritic cells (DCs). Although DCs are not direct targets for infection by EBV, we tested whether EBV antigens are cross-presented by human DCs and whether DCs are efficient at stimulation of EBV-specific CD8⁺ T cells. We show that DCs cross-presenting apoptotic or necrotic lymphoblastoid cell lines (LCLs) are able to expand CD8⁺ T cells that directly recognize HLA-matched LCLs by IFN-γ secretion and cytolytic activity. Part of this EBV-specific CDS⁸⁺ T cell response was specific for the EBV nuclear antigen EBNA3A and the latent membrane protein LMP2a. Both these antigens are expressed in PTLPD. In other EBV-associated malignancies such as Hodgkin’ s lymphoma, T cell lymphoma and nasopharyngeal carcinoma, LMP2a is maintained. Therefore, the cross-presenting ability of DCs might be explored in DC-mediated active immunization against EBV-associated malignancies. Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs) for the induction of T cell immunity [1]. In their immature state they are highly efficient in antigen uptake, using several pathways, such as macropinocytosis [2], receptor-mediated endocytosis [3] and phagocytosis of apoptotic and necrotic cell fragments [4]. The exposure to the antigen/pathogen induces the immature DC to undergo phenotypic and functional changes that lead to maturation. This enables the DCs to process the antigen onto MHC molecules, to upregulate costimulatory molecules and to secrete T cell stimulatory cytokines [1].