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 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 (sometimes after further trimming) bind to class I molecules 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 T CD8+ responses to virus 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 CD8 positive T-cell responses. To understand this phenomenon, we continue to investigate the various factors that contribute to immunodominance, including antigen processing and presentation of viral proteins, T cell regulation, and the T cell receptor repertoire. This year we have found that the multi-tRNA-aminoacyl synthetase complex specificity can be modulated at the level of individual mRNAs to alter coding of specific gene products.
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