The HLA-A2 restricted T cell epitope HCV core 35-44 stabilizes HLA-E expression and inhibits cytolysis mediated by natural killer cells

Am J Pathol. 2005 Feb;166(2):443-53. doi: 10.1016/S0002-9440(10)62267-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amino Acid Motifs
  • Antigens, CD / biosynthesis
  • Cell Membrane / metabolism
  • Cell Separation
  • Chromium Radioisotopes / chemistry
  • Epitopes / chemistry
  • Flow Cytometry
  • HLA Antigens / biosynthesis*
  • HLA Antigens / chemistry
  • HLA-A2 Antigen / metabolism*
  • Histocompatibility Antigens Class I / biosynthesis*
  • Histocompatibility Antigens Class I / chemistry
  • Humans
  • K562 Cells
  • Killer Cells, Natural / metabolism*
  • Lectins, C-Type / biosynthesis
  • Ligands
  • Liver / pathology
  • NK Cell Lectin-Like Receptor Subfamily D
  • Peptides / chemistry
  • Protein Binding
  • Time Factors
  • Transfection
  • Viral Core Proteins / chemistry*

Substances

  • Antigens, CD
  • Chromium Radioisotopes
  • Epitopes
  • HLA Antigens
  • HLA-A2 Antigen
  • HLA-E antigen
  • Histocompatibility Antigens Class I
  • KLRD1 protein, human
  • Lectins, C-Type
  • Ligands
  • NK Cell Lectin-Like Receptor Subfamily D
  • Peptides
  • Viral Core Proteins
  • nucleocapsid protein, Hepatitis C virus