MHC class I-independent recognition of NK-activating receptor KIR2DS4

Gil Katz, Roi Gazit, Tal I. Arnon, Tsufit Gonen-Gross, Gabi Tarcic, Gal Markel, Raizy Gruda, Hagit Achdout, Olga Drize, Sharon Merims, Ofer Mandelboim*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

84 Scopus citations


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 ICIRs) 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 languageAmerican English
Pages (from-to)1819-1825
Number of pages7
JournalJournal of Immunology
Issue number3
StatePublished - 1 Aug 2004


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