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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.

Original publication

DOI

10.4049/jimmunol.173.3.1819

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

08/2004

Volume

173

Pages

1819 - 1825

Addresses

Lautenberg Center for General and Tumor Immunology, Hadassah Medical School, Hebrew University, Jerusalem, Israel.

Keywords

Killer Cells, Natural, COS Cells, Cell Line, Tumor, Animals, Cercopithecus aethiops, Humans, Melanoma, Immunoglobulin G, Receptors, Immunologic, Neoplasm Proteins, Recombinant Fusion Proteins, Histocompatibility Antigens Class I, HLA-C Antigens, Ligands, Transfection, Mutagenesis, Site-Directed, Sequence Alignment, Cytotoxicity, Immunologic, Binding Sites, Amino Acid Sequence, Protein Conformation, Protein Binding, Sequence Homology, Amino Acid, Models, Molecular, Molecular Sequence Data, Immunoglobulin Fc Fragments, Receptors, KIR