Class I molecules of the major histocompatibility complex (MHC) bind antigens and present them to T cells bearing CD8 molecules. CD8 positive T-cells play a critical role in eradicating intracellular pathogens (particularly viruses) and tumors. They can also contribute to immunopathology, being involved in organ rejection and autoimmune diseases. There has been extensive progress in understanding the physical nature of the antigen-class I complex, and in how antigens are generated and become associated with class I molecules in cells. Peptides of 8 to 15 residues produced from a cytosolic pool of proteins by cytosolic proteases are translocated into the endoplasmic reticulum (ER) by a MHC encoded transporter complex known as TAP. Once in the ER, peptides (sometimes after further trimming) bind to class I molecules and are transported to the cell surface. This project aims to understand how peptides are generated, delivered and assembled with MHC class I molecules. In addition, one of the curious features of T CD8+ responses to virus infections is that it typically focuses on a highly limited set of peptides. This phenomenon, termed immunodominance, is crucial to understand if we are to develop vaccines that optimally elicit CD8 positive T-cell responses. To better understand antigen presentation and the phenomenon of immunodominance, we continue to investigate the various factors that contribute to immunodominance, including antigen processing and presentation of viral proteins, T cell regulation, and the T cell receptor repertoire. This year we have found that the tRNA deacylation can be uncoupled from protein synthesis in an amino acid specific manner (Cys). This suggests that tRNA (Cys) may have a translation independent function.

Project Start
Project End
Budget Start
Budget End
Support Year
25
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
Hickman, Heather D; Reynoso, Glennys V; Ngudiankama, Barbara F et al. (2013) Anatomically restricted synergistic antiviral activities of innate and adaptive immune cells in the skin. Cell Host Microbe 13:155-68

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