Class I molecules of the major histocompatibility complex (MHC) bind short peptides and present them to CD8+ T cells. CD8 positive T-cells play a critical role in eradicating intracellular pathogens (particularly viruses) and tumors. Nearly all viral peptides appear to derive from DRiPs (defective ribosomal products); rapidly degraded nascent proteins that fail to achieve a stable native conformation due to mistranslation, misfolding, mistargeting, or stoichiometric excess. We are characterizing all aspects of DRiP synthesis, degradation, and loading of DRiP-derived peptides onto class I molecules in the endoplasmic reticulum, the site of class I biogenesis. Following activation, lymphocytes can divide at dizzying rates (with cell cycles as rapid as 2 hr). We are studying the adaptions in translation that make this possible. Our findings suggest that the assumption that lymphocytes must synthesize all of the proteins required for division may not be true. Many other immune cells also demonstrate greatly increased translation following activation by viral infections or other insults. We are using a newly developed technique to study immune cell activation in tissue sections and also via flow cytometry, which has led to novel insights into immune cell function.

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Hickman, Heather D; Mays, Jacqueline W; Gibbs, James et al. (2018) Influenza A Virus Negative Strand RNA Is Translated for CD8+ T Cell Immunosurveillance. J Immunol 201:1222-1228
Bastide, Amandine; Yewdell, Jonathan W; David, Alexandre (2018) The RiboPuromycylation Method (RPM): an Immunofluorescence Technique to Map Translation Sites at the Sub-cellular Level. Bio Protoc 8:
Wei, Jiajie; Yewdell, Jonathan W (2018) Peptide secretion triggers diabetes. Nature 560:33-34
Morel, Jean-David; Paatero, Anja O; Wei, Jiajie et al. (2018) Proteomics Reveals Scope of Mycolactone-mediated Sec61 Blockade and Distinctive Stress Signature. Mol Cell Proteomics 17:1750-1765
Kosik, Ivan; Ince, William L; Gentles, Lauren E et al. (2018) Influenza A virus hemagglutinin glycosylation compensates for antibody escape fitness costs. PLoS Pathog 14:e1006796
Kvistborg, Pia; Yewdell, Jonathan W (2018) Enhancing responses to cancer immunotherapy. Science 359:516-517
Bastide, Amandine; Yewdell, Jonathan W; David, Alexandre (2018) Determining Ribosome Translational Status by Ribo-ELISA. Bio Protoc 8:
Wei, Jiajie; Yewdell, Jonathan W (2018) Immunoribosomes: Where's there's fire, there's fire. Mol Immunol :
Wei, Jiajie; Yewdell, Jonathan W (2017) Autoimmune T cell recognition of alternative-reading-frame-encoded peptides. Nat Med 23:409-410
Wei, Jiajie; Zanker, Damien; Di Carluccio, Anthony R et al. (2017) Varied Role of Ubiquitylation in Generating MHC Class I Peptide Ligands. J Immunol 198:3835-3845

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