title: Mixed proteasomes function to increase viral peptide diversity and broaden antiviral CD8+ T cell responses.
abstract: The three proteasome subunits with proteolytic activity are encoded by standard or immunoproteasome genes. Many proteasomes expressed by normal cells and cells exposed to cytokines are "mixed", that is, contain both standard and immunoproteasome subunits. Using a panel of 38 defined influenza A virus-derived epitopes recognized by C57BL/6 mouse CD8(+) T cells, we used mice with targeted disruption of β1i, β2i, or β5i/β2i genes to examine the contribution of mixed proteasomes to the immunodominance hierarchy of antiviral CD8(+) T cells. We show that each immunoproteasome subunit has large effects on the primary and recall immunodominance hierarchies due to modulating both the available T cell repertoire and generation of individual epitopes as determined both biochemically and kinetically in Ag presentation assays. These findings indicate that mixed proteasomes function to enhance the diversity of peptides and support a broad CD8(+) T cell response.
authors.affiliation: School of Molecular Science, La Trobe University, Bundoora, Victoria 3086, Australia.
authors.forename: Damien
authors.initials: D
authors.lastname: Zanker
authors.forename: Jason
authors.initials: J
authors.lastname: Waithman
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Yewdell
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000821:virology*; D018920:Coculture Techniques; D009980:Influenza A virus / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000201:enzymology / Q000276:immunology / Q000517:prevention & control; D010452:Peptide Biosynthesis / Q000235:genetics / Q000276:immunology; D046988:Proteasome Endopeptidase Complex / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000276:immunology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
chemical_list: D014764:Viral Proteins; D046988:Proteasome Endopeptidase Complex