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
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
Zanker, Damien; Waithman, Jason; Yewdell, Jonathan W et al. (2013) Mixed proteasomes function to increase viral peptide diversity and broaden antiviral CD8+ T cell responses. J Immunol 191:52-9
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
Stewart-Jones, Guillaume; Wadle, Andreas; Hombach, Anja et al. (2009) Rational development of high-affinity T-cell receptor-like antibodies. Proc Natl Acad Sci U S A 106:5784-8