title: KIR2DL4 is an IL-2-regulated NK cell receptor that exhibits limited expression in humans but triggers strong IFN-gamma production.
abstract: Killer cell Ig-like receptor (KIR)2DL4 (2DL4, CD158d) was previously described as the only KIR expressed by every human NK cell. It is also structurally atypical among KIRs because it possesses a basic transmembrane residue, which is characteristic of many activating receptors, but also contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM). We expressed epitope-tagged 2DL4 in an NK-like cell line to study receptor function. Three distinct 2DL4 cDNA clones were analyzed: one encoding the "conventional" 2DL4 with the cytoplasmic ITIM (2DL4.1) and two encoding different cytoplasmic truncated forms lacking the ITIM (2DL4.2 and 2DL4(*)). Surprisingly, one truncated receptor (2DL4.2), which is the product of a prevalent human 2DL4 allele, was not expressed on the cell surface, indicating that some individuals may lack functional 2DL4 protein expression. Conversely, both 2DL4.1 and 2DL4(*) were expressed on the cell surface and up-regulated by IL-2. Analysis of primary NK cells with anti-2DL4 mAb confirmed the lack of surface expression in a donor with the 2DL4.2 genotype. Donors with the 2DL4.1 genotype occasionally expressed receptor only on CD56(high) NK cells, although their expression was up-regulated by IL-2. Interestingly, Ab engagement of epitope-tagged 2DL4 triggered rapid and robust IFN-gamma production, but weak redirected cytotoxicity in an NK-like cell line, which was the opposite pattern to that observed upon engagement of another NK cell activating receptor, NKp44. Importantly, both 2DL4.1 and 2DL4(*) exhibited similar activation potential, indicating that the ITIM does not influence 2DL4.1 activating function. The unique activation properties of 2DL4 suggest linkage to a distinct signaling pathway.
mesh_terms: D000276:Adjuvants, Immunologic / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003593:Cytoplasm / Q000276:immunology / Q000378:metabolism; D053938:DNA Fragmentation / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000494:pharmacology / Q000502:physiology*; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008969:Molecular Sequence Data; D055629:Natural Cytotoxicity Triggering Receptor 2; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D054340:Receptors, KIR; D054345:Receptors, KIR2DL4; D012190:Retroviridae / Q000235:genetics / Q000276:immunology; D014161:Transduction, Genetic; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D007376:Interleukin-2; C515079:KIR2DL4 protein, human; C112837:NCR2 protein, human; D055629:Natural Cytotoxicity Triggering Receptor 2; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054345:Receptors, KIR2DL4; D019014:fas Receptor; D014443:Tyrosine; D007371:Interferon-gamma