title: MHC class I-independent recognition of NK-activating receptor KIR2DS4.
abstract: Natural killer cells are capable of killing tumor and virus-infected cells. This killing is mediated primarily via the natural cytotoxicity receptors, including NKp46, NKp44, NKp30, and by the NKG2D receptor. Killer cell Ig-like receptors (KIRs) are mainly involved in inhibiting NK killing (inhibitory KIRs) via interaction with MHC class I molecules. Some KIRs, however, have been found to enhance NK killing when interacting with MHC class I molecules (activating KIRs). We have previously demonstrated that KIR2DS4, an activating KIR, recognizes the HLA-Cw4 protein. The interaction observed was weak and highly restricted to HLA-Cw4 only. These findings prompted us to check whether KIR2DS4 might have additional ligand(s). In this study, we show that KIR2DS4 is able to also interact with a non-class I MHC protein expressed on melanoma cell lines and on a primary melanoma. This interaction is shown to be both specific and functional. Importantly, site-directed mutagenesis analysis reveals that the amino acid residues involved in the recognition of this novel ligand are different from those interacting with HLA-Cw4. These results may shed new light on the function of activating KIRs and their relevance in NK biology.
authors.affiliation: Lautenberg Center for General and Tumor Immunology, Hadassah Medical School, Hebrew University, Jerusalem, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Katz
authors.forename: Roi
authors.initials: R
authors.lastname: Gazit
authors.forename: Tal I
authors.initials: TI
authors.lastname: Arnon
authors.forename: Tsufit
authors.initials: T
authors.lastname: Gonen-Gross
authors.forename: Gabi
authors.initials: G
authors.lastname: Tarcic
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
authors.forename: Raizy
authors.initials: R
authors.lastname: Gruda
authors.forename: Hagit
authors.initials: H
authors.lastname: Achdout
authors.forename: Olga
authors.initials: O
authors.lastname: Drize
authors.forename: Sharon
authors.initials: S
authors.lastname: Merims
authors.forename: Ofer
authors.initials: O
authors.lastname: Mandelboim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D045744:Cell Line, Tumor / Q000276:immunology; D002522:Chlorocebus aethiops; D003602:Cytotoxicity, Immunologic; D015236:HLA-C Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008545:Melanoma / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009363:Neoplasm Proteins / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D054340:Receptors, KIR; D011993:Recombinant Fusion Proteins / Q000276:immunology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D015236:HLA-C Antigens; C039966:HLA-C*04 antigen; D015395:Histocompatibility Antigens Class I; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; C473953:KIR2DS4 protein, human; D008024:Ligands; D009363:Neoplasm Proteins; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D011993:Recombinant Fusion Proteins