A potential shortcoming of non-live vaccines is their relative inefficiency in generating T cell responses, thus limiting their application in infections requiring cellular immunity. Here, we present a novel system to induce cellular immunity and to study the immunological implications of time-delayed dendritic cell (DC) apoptosis and antigen reprocessing in vivo. We generated a self-replicating cytopathic pestivirus RNA to enhance production and presentation of hepatitis C virus (HCV) antigens and to induce apoptosis in DC 24-48 hours after transfection. Replicon-transfected H-2b DCs used to immunize HLA-A2 transgenic mice induced protection upon challenge with a vaccinia virus expressing HCV antigens. Induction of cell death enhanced the immunogenicity of DC-associated antigen. Transfer of cellular material from vaccine DCs to endogenous antigen presenting cells was visualized in lymph nodes and spleen and crossprimed CD8+ T cells were characterized. The findings are relevant for the rational design of vaccines against noncytopathic pathogens like HCV.