Cutting edge: the human cytomegalovirus UL40 gene product contains a ligand for HLA-E and prevents NK cell-mediated lysis.
Human CMV has evolved multiple strategies to interfere with immune recognition of the host. A variety of mechanisms target Ag presentation by MHC class I molecules resulting in a reduced class I cell-surface expression. This down-regulation of class I molecules is expected to trigger NK cytotoxicity, which would have to be counteracted by the virus to establish long-term infection. Here we describe that the human CMV open reading frame UL40 encodes a canonical ligand for HLA-E, identical with the HLA-Cw03 signal sequence-derived peptide. Expression of UL40 in HLA-E-positive target cells conferred resistance to NK cell lysis via the CD94/NKG2A receptor. Generation of the UL40-derived HLA-E ligand was also observed in TAP-deficient cells. The presence of a functional TAP-independent HLA-E ligand in the UL40 signal sequence implicates this viral gene as an important negative regulator of NK activity.
Ulbrecht
M
M
Institut für Anthropologie und Humangenetik, Munich, Germany.
Martinozzi
S
S
Grzeschik
M
M
Hengel
H
H
Ellwart
J W
JW
Pla
M
M
Weiss
E H
EH
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000821:virology; D006680:HLA Antigens / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008969:Molecular Sequence Data; D009842:Oligopeptides; D016366:Open Reading Frames / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology / Q000302:isolation & purification; D010455:Peptides / Q000276:immunology; D011499:Protein Processing, Post-Translational / Q000276:immunology; D014162:Transfection; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000097625:HLA-E Antigens
D000911:Antibodies, Monoclonal; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D008024:Ligands; D009842:Oligopeptides; D010446:Peptide Fragments; D010455:Peptides; D014764:Viral Proteins; D000097625:HLA-E Antigens; C404228:UL40 glycoprotein, Cytomegalovirus; C085706:FLAG peptide