CD8 positive T-lymphocytes play an important role in host immunity to viruses. Anti-viral CD8+ T-cells recognize MHC class I molecules bound to peptides derived from a cytosolic pool of viral proteins. Concerning the delivery of antigenic peptides to MHC class I molecules, our studies have addressed the following specific questions. First, there are two sources of antigenic peptides, native proteins and everything else. We have termed all the non-native sources, DRiPs, or defective ribosomal products and rapidly degraded proteins. DRiPs consist of prematurely terminated polypeptides and misfolded polypeptides produced from translation products of bona fide mRNAs in the proper reading frame. We have been analyzing the contribution of DRiPs to antigen presentation in viral infections. Second this project will examine the nature of the substrate from which antigenic peptides are derived and their contribution to antigen presentation. Third, these studies will examine potential mechanisms of delivering antigen to the class I processing pathway. This year we have examined the extent to which viruses manipulate cellular tRNA populations and found that the polysome-associated tRNA population change dramatically in a virus-specific manner to reflect the codon usage of viral genes. This suggests the existence of local tRNA pools optimized for viral translation.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2013
Total Cost
$375,747
Indirect Cost
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State
Country
Zip Code
Anton, Luis C; Yewdell, Jonathan W (2014) Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors. J Leukoc Biol 95:551-62
Pavon-Eternod, Mariana; David, Alexandre; Dittmar, Kimberly et al. (2013) Vaccinia and influenza A viruses select rather than adjust tRNAs to optimize translation. Nucleic Acids Res 41:1914-21
Kim, Yohan; Yewdell, Jonathan W; Sette, Alessandro et al. (2013) Positional bias of MHC class I restricted T-cell epitopes in viral antigens is likely due to a bias in conservation. PLoS Comput Biol 9:e1002884
Goldszmid, Romina S; Coppens, Isabelle; Lev, Avital et al. (2009) Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells. J Exp Med 206:399-410