Engineered apoptosis as an immune adjuvant: The use of DR5 as an immune adjuvant

Recent reports have suggested that unlike the constitutively ongoing, homeostatic-apoptotic process (the orderly de-construction of a cell), non-homeostatic apoptosis of tissues in vivo is associated with an inflammatory response. Further, as shown in several in vitro studies, the proteins/peptides carried in apoptotic bodies generated by non-homeostatic apoptosis appear to be processed and cross-presented by dendritic cells much more efficiently than their non-homeostatic counterparts. We hypothesize that in the presence of foreign antigens, the apoptotic-inflammatory process acts as an immune-adjuvant, facilitating immune priming to foreign antigens and improving vaccine immunity. Using the technique of plasmid immunization to transfect myocytes in vivo and express a vaccine antigen, we investigated the concept of pro-apoptotic molecules as immune adjuvants. We used the well-defined pro-apoptotic members of the Tumor Necrosis Factor Receptor Superfamily (TNFR-SF) to induce apoptosis, but focused on the death-inducing molecules whose ligands are found on dendritic cells. These molecules were compared to the non-apoptotic members of this family. In comparative studies of immune adjuvancy, the TNFR-SF molecules were co-immunized as plasmids along with the plasmid expressing the vaccine antigen. We show a significant improvement in T-cell mediated vaccine immunity using this strategy. All pro-apoptotic members of the TNFR-SF were able to improve CD8+ T-cell vaccine immunity with varying degrees of potency, more varied effects were found with regard to CD4+ T-cell priming. In particular, DR5/TRAIL-R2 was a very potent adjuvant. We further demonstrate that the adjuvant activity of DR5 is associated with its ability to induce apoptosis in vivo. None of the non-apoptotic TNFR-SF molecules tested had any effect on CD8+ T-cell priming, and only Ox40 had an adjuvant effect on CD4+ T-cell and B-cell priming. We suggest that apoptosis in vivo induced by intracellular organisms, or artificially in such vaccine regimens may serve as an important natural immune adjuvant for CD8+ T cell immunity. Furthermore, we describe a novel function of the TRAIL-DR5 pathway: serving as a link between the innate and adaptive immune system, where the generation of apoptotic fragments from infected cells improves immune priming to foreign antigens in vivo.