title: A viral, transporter associated with antigen processing (TAP)-independent, high affinity ligand with alternative interactions endogenously presented by the nonclassical human leukocyte antigen E class I molecule.
abstract: The transporter associated with antigen processing (TAP) enables the flow of viral peptides generated in the cytosol by the proteasome and other proteases to the endoplasmic reticulum, where they complex with nascent human leukocyte antigen (HLA) class I. Later, these peptide-HLA class I complexes can be recognized by CD8(+) lymphocytes. Cancerous cells and infected cells in which TAP is blocked, as well as individuals with unusable TAP complexes, are able to present peptides on HLA class I by generating them through TAP-independent processing pathways. Here, we identify a physiologically processed HLA-E ligand derived from the D8L protein in TAP-deficient vaccinia virus-infected cells. This natural high affinity HLA-E class I ligand uses alternative interactions to the anchor motifs previously described to be presented on nonclassical HLA class I molecules. This octameric peptide was also presented on HLA-Cw1 with similar binding affinity on both classical and nonclassical class I molecules. In addition, this viral peptide inhibits HLA-E-mediated cytolysis by natural killer cells. Comparison between the amino acid sequences of the presenting HLA-E and HLA-Cw1 alleles revealed a shared structural motif in both HLA class molecules, which could be related to their observed similar cross-reactivity affinities. This motif consists of several residues located on the floor of the peptide-binding site. These data expand the role of HLA-E as an antigen-presenting molecule.
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Lorente
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Infantes
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Abia
authors.affiliation: Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Eilon
authors.initials: E
authors.lastname: Barnea
authors.affiliation: IBM Haifa Research Lab, Haifa 31905, Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Beer
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: Ruth
authors.initials: R
authors.lastname: García
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: Fátima
authors.initials: F
authors.lastname: Lasala
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Jiménez
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Mir
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas (CSIC)/Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Morreale
authors.affiliation: Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Arie
authors.initials: A
authors.lastname: Admon
authors.affiliation: Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain. Electronic address: dlopez@isciii.es.
authors.forename: Daniel
authors.initials: D
authors.lastname: López
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020816:Amino Acid Motifs; D017951:Antigen Presentation; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014615:Vaccinia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015678:Viral Structural Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000097625:HLA-E Antigens
chemical_list: D018528:ATP-Binding Cassette Transporters; D000956:Antigens, Viral; D015236:HLA-C Antigens; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D010455:Peptides; D015678:Viral Structural Proteins; D000097625:HLA-E Antigens; C528011:D8L protein, vaccinia virus; C047431:HLA-Cw1 antigen; C477327:transporter associated with antigen processing (TAP)