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




Journal article


J Immunol

Publication Date





1819 - 1825


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