Cutting edge: Induction of enhanced CTL-dependent protective immunity in vivo by N-end rule targeting of a model tumor antigen

There is much interest in vaccines that will enhance the induction of CTL. One mechanism to enhance Ag-specific CTL responses involves targeting Ag to undergo rapid cytoplasmic degradation by the N-end rule pathway. We have a nalyzed the ability of N-end rule targeting to confer protection in an immu nization-challenge setting. Using the HIV-1 nef protein as a model tumor Ag , we found that in mice immunized with a vaccinia vector expressing a form of nef that is targeted for rapid cytoplasmic degradation, there was enhanc ed induction of nef-specific CTL and protection from a lethal challenge wit h the syngeneic CT26 tumor cells that had been transfected with nef, Protec tion from tumor challenge correlated with the magnitude of the CTL response , Thus, the targeting of tumor or viral Ags for rapid cytoplasmic degradati on by the N-end rule pathway may represent a strategy for the induction of protective Ag-specific CTL responses in vivo.