Priming of pathogen-specific CDS T cell responses involves the recognition of pathogen-derived, antigenic peptides in the context of MHC class I molecules on the surface of professional antigen presenting cells (pAPC). These peptides are generated upon intracellular degradation of pathogen-derived proteins by a cellular protease complex, the proteasome. pAPC and cells exposed to inflammatory cytokines express a number of inducible proteasome components which modify the catalytic activity of proteasomes and accelerate the generation of many antigenic peptides. CDS T cell responses to infections are often focused towards single """"""""immunodominant"""""""" epitopes. Many immunodominant antigenic peptides: 1), derive from antigens that are rapidly degraded within host cells;and 2), are rapidly generated by the modified form of the proteasome. Based on these observations, we propose that these antigenic peptides that appear the earliest on the cell surface of pAPC following infection will be the most potent in inducing CDS T-cell responses.
In aim 1 we will test this hypothesis by infecting normal and genetically modified mice that lack the inducible proteasome components with recombinant Listeria monocytogenes. CDS T-cell responses to rapidly and slowly degraded Listeria antigens and to rapidly and slowly generated Listeria peptides will be examined. Our studies will show whether the relative rates with which antigenic peptides are generated determine their capacity to prime CDS T cell responses.
In aim 2, we will determine in which cells immunodominance is decided. Mice that express the inducible proteasome components in specific cell types only will be generated and tested for their ability to mount responses to peptides that are inefficiently generated by the unmodified type of proteasome. These experiments will show whether antigen processing events in infected cells or in cross-presenting pAPC are decisive for the priming of CDS T cell responses. These studies will enlarge our understanding of the determinants of immunodominance and are of great importance for vaccine design.
