Class I molecules of the major histocompatibility complex (MHC) consist of a highly polymorphic heavy chain complexed to beta2 microglobulin (beta2m). Class I molecules are constitutively expressed by numerous cell types in the body. Expression by non-expressing cell types occurs rapidly in the course of a immune response following exposure to gamma- IFN and other cytokines. The sole function of class I molecules is to bind antigens and present them to T cell bearing CD8 molecules (T/CD8+). T/CD8+ play a critical role in eradicating intracellular pathogens 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 by peptidases) bind to class I molecules associated with TAP and are transported to the cell surface. In the past year we have continued our studies the assembly and trafficking of MHC class I molecules and have made progress on a number of fronts: 1) We developed fluorescent derivatives of an antigenic peptides and used these probes to make several novel findings about the intracellular trafficking of class I molecules and antigenic peptides, 2) We have studied the intracellular trafficking of class I molecules using [3H]-labeled saccharides to label class I associated N-linked oligosaccharides.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000542-08
Application #
5200500
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
1995
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
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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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