CD8 expressing T cells play a critical role in eradicating intracellular parasites such as viruses. CD8 positive T cells recognize MHC class I molecules in a complex with peptides of 8 to 10 residues derived from viral proteins located in the cytosol. There is tremendous interest in the mechanism by which peptides are generated. Indirect evidence implicates proteasomes in the generation of antigenic peptides. Proteasomes are abundant macromolecular structures present in the cytosol and nucleus, and have multiple protease activities. They are thought to be responsible for energy dependent proteolysis in which ubiquitin plays a prominent role in targeting proteins for destruction. In this project we examine the contribution of proteasomes to the production of antigenic peptides as well as their importance to viral life cycles. Another goal is to identify sequences that enhance the immunogenicity of proteins by increasing their capacity to generate antigenic peptides. This year we have found evidence for distinct pathways for presentation of DRiPs versus mature native proteins. In addition the results have implicated polyubiquitin chain disassembly or the actions of deubiquitylating enzymes as playing an important role in DRiP presentation.
