The role of tripeptidyl peptidase II in MHC class I-restricted antigen processing and the effect of epitope density of CD8(+) T cell priming
CD8+ T cells (TCD8+) recognize peptides displayed at the cell surface by MHC class I molecules. The generation and presentation of the appropriate number of properly processed peptides is crucial for an effective TCD8+ response. The generation of many antigenic peptides occurs by limited cytosolic proteolysis by the proteasome. However, in some cases epitope presentation is unaffected or enhanced in the presence of inhibitors of the proteasome suggesting the involvement of other rate limiting proteases. Tripeptidyl peptidase II (TPP II) is a large protease that may compensate when essential functions of the proteasome, are compromised. We have examined the potential of TPP II to contribute to the processing and presentation of 2 CTL epitopes with distinct presentation phenotypes in the presence of proteasome inhibitors. Results employing both protease inhibitors of TPP II and a specific TPP II overexpression system suggest that TPP II does not constitute a rate limiting protease capable of non-proteasomal antigen processing. However, the results of protease inhibitor experiments suggest that TPP II may contribute to epitope generation at a non limiting step in the pathway, perhaps downstream of initial proteasomal cleavage. The efficiency of intracellular antigen processing may greatly impact cell surface epitope density. However, because of difficulties altering only epitope levels, no consensus exists regarding the impact of this variable on the priming of naïve TCD8+ in vivo. Yet approaches have been designed to increase epitope expression levels during TCD8+ priming to optimize responses. We have examined the influence of epitope expression level on the priming of TCD8+ using a system that allows the expression of a 200-fold range of epitope during similar vaccinia (vac) infections. The results demonstrate that the magnitude of a TCD8+ response generated in vivo is proportional to epitope density and steadily rises as epitope expression increases. However, at the highest epitope expression level this relationship breaks down leading to a decrease in the magnitude of the TCD8+ population. The mechanisms of antigen processing will directly impact the efficiency of epitope presentation. Understanding the mechanisms of proteolysis and the impact of changes in cell surface epitope density upon TCD8+ induction may offer clues to optimizing TCD8+ responses to intracellular pathogens.
Wherry, Edward John, "The role of tripeptidyl peptidase II in MHC class I-restricted antigen processing and the effect of epitope density of CD8(+) T cell priming" (1999). ProQuest ETD Collection - Thomas Jefferson University. AAI9963599.