CD8+ CTL play a critical role as effectors in limiting viral infections, conveying anti-tumor immunity, and contributing to autoimmunity. CD8+ CTL are triggered by antigen-derived peptides (epitopes) held at the surface of antigen-bearing cells by MHC class I molecules. In most cases the first step in epitope generation is degradation of antigen within the cytosol. Resultant fragments are then actively transported to the lumen of the endoplasmic reticulum where they bind to nascent MHC class I molecules provided they meet stringent length and sequence requirements. The heterotrimeric complexes are then transported to the cell surface where they are contacted by T cells with appropriate receptor specificities. In contrast to some previous findings, Dr. Eisenlohr's studies indicate that the antigen processing machinery dictates the quality of the antigenic epitopes generated. They hypothesize that 1) flanking sequences have an impact upon immunogenicity of epitopes, and that viruses and tumor cells use mutation of flanking sequences to evade CD8+ CTL; and 2) the study of proximal and distal flanking sequence effects provides valuable insight into the nature of the antigen processing machinery and powerful tools for identifying specific components of the machinery. To test these hypotheses, the investigators will: 1) determine whether there are general rules that govern the influence of sequences neighboring an epitope, 2) directly test in vivo the impact that flanking sequences have upon recruitment of CD8+ CTL precursors, memory CTL, and resistance to viral and tumor challenge, 3) determine whether the blocks in processing conferred by local flanking residues can be attributed to proteasome specificity, and whether the blocks in processing conferred by local flanking residues can be attributed to proteasome specificity and whether other proteases are implicated in antigen processing, and 4) identify and characterize sequences that strongly influence, positively and negatively, presentation of distal epitopes.
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