The HLA-A2 restricted T cell epitope HCV core 35-44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells.
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.
Nattermann
Jacob
J
Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany. Jacob.Nattermann@ukb.uni-bonn.de
Nischalke
Hans Dieter
HD
Hofmeister
Valeska
V
Ahlenstiel
Golo
G
Zimmermann
Henning
H
Leifeld
Ludger
L
Weiss
Elisabeth H
EH
Sauerbruch
Tilman
T
Spengler
Ulrich
U
D000465:Algorithms; D020816:Amino Acid Motifs; D015703:Antigens, CD / Q000096:biosynthesis; D002462:Cell Membrane / Q000378:metabolism; D002469:Cell Separation; D002860:Chromium Radioisotopes / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D006680:HLA Antigens / Q000096:biosynthesis* / Q000737:chemistry; D015789:HLA-A2 Antigen / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000378:metabolism*; D037181:Lectins, C-Type / Q000096:biosynthesis; D008024:Ligands; D008099:Liver / Q000473:pathology; D051920:NK Cell Lectin-Like Receptor Subfamily D; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D013997:Time Factors; D014162:Transfection; D014758:Viral Core Proteins / Q000737:chemistry*; D000097625:HLA-E Antigens
D015703:Antigens, CD; D002860:Chromium Radioisotopes; D000939:Epitopes; D006680:HLA Antigens; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D008024:Ligands; D051920:NK Cell Lectin-Like Receptor Subfamily D; D010455:Peptides; D014758:Viral Core Proteins; D000097625:HLA-E Antigens; C497869:KLRD1 protein, human; C069130:nucleocapsid protein, Hepatitis C virus