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 developed the ribopuromycylation method (RPM), which visualizes translation in cells via standard immunofluorescence microscopy. We have used RPM to provide evidence for translation in the nucleoplasm and nucleolus, which is regulated by infectious and chemical stress.

Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2012
Total Cost
$248,901
Indirect Cost
City
State
Country
Zip Code
David, Alexandre; Yewdell, Jonathan W (2015) Applying the ribopuromycylation method to detect nuclear translation. Methods Mol Biol 1228:133-42
Shastri, Nilabh; Yewdell, Jonathan W (2015) Editorial overview: Antigen processing and presentation: Where cellular immunity begins. Curr Opin Immunol 34:v-vii
Wei, Jiajie; Gibbs, James S; Hickman, Heather D et al. (2015) Ubiquitous Autofragmentation of Fluorescent Proteins Creates Abundant Defective Ribosomal Products (DRiPs) for Immunosurveillance. J Biol Chem 290:16431-9
Anton, Luis C; Yewdell, Jonathan W (2014) Translating DRiPs: MHC class I immunosurveillance of pathogens and tumors. J Leukoc Biol 95:551-62
Hickman, Heather D; Yewdell, Jonathan W (2013) Going Pro to enhance T-cell immunogenicity: easy as ýý? Eur J Immunol 43:2814-7
Gilchuk, Pavlo; Spencer, Charles T; Conant, Stephanie B et al. (2013) Discovering naturally processed antigenic determinants that confer protective T cell immunity. J Clin Invest 123:1976-87
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
Yewdell, Jonathan W; David, Alexandre (2013) Nuclear translation for immunosurveillance. Proc Natl Acad Sci U S A 110:17612-3
Yewdell, Jonathan W (2013) Amsterdamming DRiPs. Mol Immunol 55:110-2
Graber, Tyson E; Hébert-Seropian, Sarah; Khoutorsky, Arkady et al. (2013) Reactivation of stalled polyribosomes in synaptic plasticity. Proc Natl Acad Sci U S A 110:16205-10

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