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 tremendous interest in the mechanism 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 proteasomes and 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 proteolytically generated, delivered and assembled with MHC class I molecules as well as the cell biology of trafficking to the cell surface. It further examines the implications of antigen processing and presentation for anti-viral CD8+ T cell recognition and the affects of inhibitory viral proteins on the processing pathway. This year we have found peptide specific clustering of MHC class I molecules at the cell surface and have proposed that endogenous processing generates these peptide-specific clusters of class I molecules to maximize the sensitivity and speed of T-cell immunosurveillance.

Project Start
Project End
Budget Start
Budget End
Support Year
26
Fiscal Year
2013
Total Cost
$375,746
Indirect Cost
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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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