title: Rapid antigen processing and presentation of a protective and immunodominant HLA-B*27-restricted hepatitis C virus-specific CD8+ T-cell epitope.
abstract: HLA-B*27 exerts protective effects in hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections. While the immunological and virological features of HLA-B*27-mediated protection are not fully understood, there is growing evidence that the presentation of specific immunodominant HLA-B*27-restricted CD8+ T-cell epitopes contributes to this phenomenon in both infections. Indeed, protection can be linked to single immunodominant CD8+ T-cell epitopes and functional constraints on escape mutations within these epitopes. To better define the immunological mechanisms underlying HLA-B*27-mediated protection in HCV infection, we analyzed the functional avidity, functional profile, antiviral efficacy and naïve precursor frequency of CD8+ T cells targeting the immunodominant HLA-B*27-restricted HCV-specific epitope as well as its antigen processing and presentation. For comparison, HLA-A*02-restricted HCV-specific epitopes were analyzed. The HLA-B*27-restricted CD8+ T-cell epitope was not superior to epitopes restricted by HLA-A*02 when considering the functional avidity, functional profile, antiviral efficacy or naïve precursor frequency. However, the peptide region containing the HLA-B*27-restricted epitope was degraded extremely fast by both the constitutive proteasome and the immunoproteasome. This efficient proteasomal processing that could be blocked by proteasome inhibitors was highly dependent on the hydrophobic regions flanking the epitope and led to rapid and abundant presentation of the epitope on the cell surface of antigen presenting cells. Our data suggest that rapid antigen processing may be a key immunological feature of this protective and immunodominant HLA-B*27-restricted HCV-specific epitope.
authors.affiliation: Department of Medicine II, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schmidt
authors.forename: Astrid K N
authors.initials: AK
authors.lastname: Iversen
authors.forename: Stefan
authors.initials: S
authors.lastname: Tenzer
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Volker
authors.initials: V
authors.lastname: Lohmann
authors.forename: Ute
authors.initials: U
authors.lastname: Distler
authors.forename: Paul
authors.initials: P
authors.lastname: Bowness
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Paul
authors.initials: P
authors.lastname: Klenerman
authors.forename: Christoph
authors.initials: C
authors.lastname: Neumann-Haefelin
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D015235:HLA-B Antigens / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology*; D018936:Hepatitis C Antigens / Q000276:immunology*; D006801:Humans; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D059748:Proteolysis
chemical_list: D000939:Epitopes; D015235:HLA-B Antigens; D018936:Hepatitis C Antigens; D046988:Proteasome Endopeptidase Complex