Protection of mice against Friend retrovirus infection by vaccination with antigen-loaded, spleen-derived dendritic cells.

Antigen-loaded dendritic cells (DC) have been shown to induce specific immune responses in vivo. In the current study we used Friend virus (FV) as a model to analyze whether a DC vaccine is capable of inducing protective immunity against retroviral infections. Mice were vaccinated twice with spleen-derived DC loaded with FV antigen. All control mice that received DC without antigen developed progressive leukemia after FV challenge. In contrast, five of the 14 vaccines were protected against infection, three recovered from FV-induced disease, and only six progressed to lethal leukemia. Animals that progressed to disease had high viral loads in blood and spleen similar to the control mice. Virus-specific antibody responses were not induced by DC vaccination. In contrast, protection correlated with a vaccine-induced CD8+ T-cell response directed against an immunodominant epitope of FV. CD8+ T-cells were critical for the protective effect of the DC vaccine, since in vivo depletion of these cells from immunized mice prevented their protection. Our results demonstrate that antigen-loaded DC can induce specific cellular immune responses and prevent retrovirus-induced disease.

MHC class II-mediated apoptosis in dendritic cells: a role for membrane-associated and mitochondrial signaling pathways.

Cytotoxic elimination of dendritic cells (DC) in lymphoid tissue represents an important pathway of immune regulation. However, the mechanism of DC removal is still controversial since mature DC are insensitive to death receptor-mediated killing and other surface or soluble molecules mediating DC death in vivo have yet to be characterized. Class II ligation is the only known signal that induces rapid cell death in mature DC, thus our studies have now focused on the requirements for this cell death using the advantages of tools available for both the mouse and human systems. Anti-class II mAb could be grouped into (i) mAb that both bound to class II and caused class II-mediated cell death as well as (ii) those that bound to class II, but did not cause apoptosis. mAb binding stable class II dimers as well as those mAb recognizing either the alpha or beta chains of class II were found in both groups. Whereas class II-mediated death was enhanced by DC-DC homotypic interactions, DC clustering itself was insufficient to induce apoptosis. Although DC death could be inhibited by uncoupling actin filament bundling, the inhibition of various proteases, including the caspases, and protein transport mediators failed to inhibit class II-mediated cell death. Neither Bid, poly-ADP-ribose polymerase, caspases-3, -7 and -8 nor FLICE-inhibitory protein were found to be cleaved during class II apoptosis. Lastly, although class II mAb induced a rapid mitochondrial membrane depolarization in DC, cell death was not inhibited by Bcl-2 over-expression in DC. The independence of this form of apoptosis from protein or RNA synthesis, coupled to the rapidity of the mitochondrial depolarization and the lack of protection by Bcl-2, suggests that mature DC express pre-formed pro-apoptotic molecules that are involved in class II-mediated death.