1. The HLA-A2 restricted T cell epitope HCV core 35-44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells.
- Author
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Nattermann J, Nischalke HD, Hofmeister V, Ahlenstiel G, Zimmermann H, Leifeld L, Weiss EH, Sauerbruch T, and Spengler U
- Subjects
- Algorithms, Amino Acid Motifs, Antigens, CD biosynthesis, Cell Membrane metabolism, Cell Separation, Chromium Radioisotopes chemistry, Epitopes chemistry, Flow Cytometry, HLA Antigens chemistry, Histocompatibility Antigens Class I chemistry, Humans, K562 Cells, Lectins, C-Type biosynthesis, Ligands, Liver pathology, NK Cell Lectin-Like Receptor Subfamily D, Peptides chemistry, Protein Binding, Time Factors, Transfection, HLA-E Antigens, HLA Antigens biosynthesis, HLA-A2 Antigen metabolism, Histocompatibility Antigens Class I biosynthesis, Killer Cells, Natural metabolism, Viral Core Proteins chemistry
- Abstract
Impaired activity of natural killer cells has been proposed as a mechanism contributing to viral persistence in hepatitis C virus (HCV) infection. Natural cytotoxicity is regulated by interactions of HLA-E with inhibitory CD94/NKG2A receptors on natural killer (NK) cells. Here, we studied whether HCV core encodes peptides that bind to HLA-E and inhibit natural cytotoxicity. We analyzed 30 HCV core-derived peptides. Peptide-induced stabilization of HLA-E expression was measured flow cytometrically after incubating HLA-E-transfected cells with peptides. NK cell function was studied with a (51)chromium-release-assay. Intrahepatic HLA-E expression was analyzed by an indirect immunoperoxidase technique and flow cytometry of isolated cells using a HLA-E-specific antibody. We identified peptide aa35-44, a well-characterized HLA-A2 restricted T cell epitope, as a peptide stabilizing HLA-E expression and thereby inhibiting NK cell-mediated lysis. Blocking experiments confirmed that this inhibitory effect of peptide aa35-44 on natural cytotoxicity was mediated via interactions between CD94/NKG2A receptors and enhanced HLA-E expression. In line with these in vitro data we found enhanced intrahepatic HLA-E expression on antigen-presenting cells in HCV-infected patients. Our data indicate the existence of T cell epitopes that can be recognized by HLA-A2 and HLA-E. This dual recognition may contribute to viral persistence in hepatitis C.
- Published
- 2005
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