NDLI: The efficiency of human cytomegalovirus pp65(495-503) CD8+ T cell epitope generation is determined by the balanced activities of cytosolic and endoplasmic reticulum-resident peptidases.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Halenius, Anne Textoris-Taube, Kathrin Ebstein, Frédéric Kessler, Jan H. Henklein, Petra Reimann, Barbara Janek, Katharina Foulon, Thierry Dannenberg, Tanja Paschke, Julia Bernhard, Helga Paschen, Annette Urban, Sabrina Seifert, Christin Zhao, Fang Ossendorp, Ferry Schadendorf, Dirk Seifert, Ulrike Cadel, Sandrine
Description	Country affiliation: Germany Author Affiliation: Urban S ( Institut für Biochemie, Charité-Universitätsmedizin, 10117 Berlin, Germany.)
Abstract	Control of human CMV (HCMV) infection depends on the cytotoxic activity of CD8(+) CTLs. The HCMV phosphoprotein (pp)65 is a major CTL target Ag and pp65(495-503) is an immunodominant CTL epitope in infected HLA-A*0201 individuals. As immunodominance is strongly determined by the surface abundance of the specific epitope, we asked for the components of the cellular Ag processing machinery determining the efficacy of pp65(495-503) generation, in particular, for the proteasome, cytosolic peptidases, and endoplasmic reticulum (ER)-resident peptidases. In vitro Ag processing experiments revealed that standard proteasomes and immunoproteasomes generate the minimal 9-mer peptide epitope as well as N-terminal elongated epitope precursors of different lengths. These peptides are largely degraded by the cytosolic peptidases leucine aminopeptidase and tripeptidyl peptidase II, as evidenced by increased pp65(495-503) epitope presentation after leucine aminopeptidase and tripeptidyl peptidase II knockdown. Additionally, with prolyl oligopeptidase and aminopeptidase B we identified two new Ag processing machinery components, which by destroying the pp65(495-503) epitope limit the availability of the specific peptide pool. In contrast to cytosolic peptidases, silencing of ER aminopeptidases 1 and 2 strongly impaired pp65(495-503)-specific T cell activation, indicating the importance of ER aminopeptidases in pp65(495-503) generation. Thus, cytosolic peptidases primarily interfere with the generation of the pp65(495-503) epitope, whereas ER-resident aminopeptidases enhance such generation. As a consequence, our experiments reveal that the combination of cytosolic and ER-resident peptidase activities strongly shape the pool of specific antigenic peptides and thus modulate MHC class I epitope presentation efficiency.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	2
Volume Number	189
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2012-07-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cd8-positive T-lymphocytes Immunology Cytomegalovirus Infections Cytosol Endoplasmic Reticulum Epitopes, T-lymphocyte Metabolism Peptide Hydrolases Antigen Presentation Enzymology Virology Cell Line Pathology Biosynthesis Toxicity Hela Cells Peptide Fragments Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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