The efficiency of human cytomegalovirus pp65495-503 CD8 +T cell epitope generation is determined by the balanced activities of cytosolic and endoplasmic reticulum-resident peptidases

Sabrina Urban, Kathrin Textoris-Taube, Barbara Reimann, Katharina Janek, Tanja Dannenberg, Frédéric Ebstein, Christin Seifert, Fang Zhao, Jan H. Kessler, Anne Halenius, Petra Henklein, Julia Paschke, Sandrine Cadel, Helga Bernhard, Ferry Ossendorp, Thierry Foulon, Dirk Schadendorf, Annette Paschen, Ulrike Seifert

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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 pp65495-503 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 pp65495-503 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 pp65495-503 epitope limit the availability of the specific peptide pool. In contrast to cytosolic peptidases, silencing of ER aminopeptidases 1 and 2 strongly impaired pp65495-503-specific T cell activation, indicating the importance of ER aminopeptidases in pp65495-503 generation. Thus, cytosolic peptidases primarily interfere with the generation of the pp65495-503 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.

Original languageEnglish
Pages (from-to)529-538
Number of pages10
JournalJournal of Immunology
Volume189
Issue number2
DOIs
StatePublished - 15 Jul 2012
Externally publishedYes

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