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 that the efficiency of antigen presentation varies dependent on whether the antigen derives from cellular or virus encoded proteins. The results suggest that the class I antigen-processing machinery can distinguish folded proteins based on the precise details of their synthesis to modulate antigen presentation efficiency.

Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2012
Total Cost
$613,798
Indirect Cost
City
State
Country
Zip Code
Yewdell, Jonathan W; Princiotta, Michael F (2012) All roads lead to ""ome"": defining the DRiPome. Blood 119:6179-80
Dolan, Brian P; Sharma, Aditi A; Gibbs, James S et al. (2012) MHC class I antigen processing distinguishes endogenous antigens based on their translation from cellular vs. viral mRNA. Proc Natl Acad Sci U S A 109:7025-30
Dolan, Brian P; Li, Lily; Veltri, Charles A et al. (2011) Distinct pathways generate peptides from defective ribosomal products for CD8+ T cell immunosurveillance. J Immunol 186:2065-72
Qian, Shu-Bing; Zhang, Xingqian; Sun, Jun et al. (2010) mTORC1 links protein quality and quantity control by sensing chaperone availability. J Biol Chem 285:27385-95
Yewdell, Jonathan W (2010) Designing CD8+ T cell vaccines: it's not rocket science (yet). Curr Opin Immunol 22:402-10
Rothenburg, Stefan; Seo, Eun Joo; Gibbs, James S et al. (2009) Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors. Nat Struct Mol Biol 16:63-70
Netzer, Nir; Goodenbour, Jeffrey M; David, Alexandre et al. (2009) Innate immune and chemically triggered oxidative stress modifies translational fidelity. Nature 462:522-6
Rosinski, Kellie V; Fujii, Nobuharu; Mito, Jeffrey K et al. (2008) DDX3Y encodes a class I MHC-restricted H-Y antigen that is expressed in leukemic stem cells. Blood 111:4817-26