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, commonly 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. In 2014, we have continued to study the trafficking of peptide specific clusters of MHC class I molecules to the cell surface and the mechanism that generates the clusters. Their importance stems form the fact that these peptide-specific clusters maximize the sensitivity and speed of T-cell immunosurveillance.

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27
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2014
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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
Magadán, Javier G (2014) Zonal Sedimentation Analysis on Sucrose Gradients. Bio Protoc 4:
Magadán, Javier G (2014) Radioactive Pulse-Chase Analysis and Immunoprecipitation. Bio Protoc 4:
Antón, 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; 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
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
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

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