Class I molecules of the major histocompatibility complex (MHC) bind antigens and present them to T cells bearing CD8 molecules (TCD8+ ). TCD8+ 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 rapid 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 (possibly after further trimming) bind to class I molecules associated with TAP 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 TCD8+ responses to viral 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 TCD8+ responses. To understand this phenomenon, we are investigating the various factors that contribute to immunodominance, including antigen processing, T cell regulation, and T cell receptor repertoire.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000542-11
Application #
6098961
Study Section
Special Emphasis Panel (LVD)
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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
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
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
David, Alexandre; Bennink, Jack R; Yewdell, Jonathan W (2013) Emetine optimally facilitates nascent chain puromycylation and potentiates the ribopuromycylation method (RPM) applied to inert cells. Histochem Cell Biol 139:501-4
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
Haeryfar, S M Mansour; Hickman, Heather D; Irvine, Kari R et al. (2008) Terminal deoxynucleotidyl transferase establishes and broadens antiviral CD8+ T cell immunodominance hierarchies. J Immunol 181:649-59
Lev, Avital; Takeda, Kazuyo; Zanker, Damien et al. (2008) The exception that reinforces the rule: crosspriming by cytosolic peptides that escape degradation. Immunity 28:787-98
Yewdell, Jonathan W (2007) Plumbing the sources of endogenous MHC class I peptide ligands. Curr Opin Immunol 19:79-86
Pardigon, Nathalie; Takeda, Kazuyo; Saunier, Bertrand et al. (2006) CD8 alpha alpha-mediated intraepithelial lymphocyte snatching of thymic leukemia MHC class Ib molecules in vitro and in vivo. J Immunol 177:1590-8
Yewdell, Jonathan W; Haeryfar, S M Mansour (2005) Understanding presentation of viral antigens to CD8+ T cells in vivo: the key to rational vaccine design. Annu Rev Immunol 23:651-82

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