The classical model of MHC class I antigen processing prescribes a critical role for the ubiquitin-proteasome system in generating peptides to display for CD8+ T cell surveillance. However, multiple exceptions to this pathway have been described. Using large-scale proteomic methods as well as model experiments, we explore 1) the non-proteasomal enzymes responsible for generating or destroying an influenza virus epitope; 2) the role of ubiquitin-independent antigen processing in shaping the MHC class I peptidome; and 3) the contribution to the MHC class I peptide repertoire of aminoglycoside-induced translational readthrough of stop codons. Our findings indicate a significant role for non-classical MHC class I antigen processing. This includes extra-proteasomal proteases we identify as destroying the influenza epitope NP147-155, as well as an impact from ubiquitin-independent pathways that challenges the centrality of the ubiquitin-proteasome system. Additionally, we demonstrate that the non-standard translational events induced by gentamicin can reveal cryptic MHC class I epitopes, with implications for autoimmunity. These observations suggest a substantial contribution from processes that operate outside of the classically described pathways of MHC class I antigen processing.
|Advisor:||Eisenlohr, Laurence C.|
|Commitee:||Calkins, Catherine E., Paumet, Fabienne, Quong, Andrew A., Waldman, Scott A.|
|School:||Thomas Jefferson University|
|Department:||Immunology and Microbial Pathogenesis|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 75/08(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Immunology|
|Keywords:||Antigen presentation, Antigen processing, Autoimmunity, Mhc class i, Proteomics, Ubiquitin|
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