KIR2DL4 is an IL-2-regulated NK cell receptor that exhibits limited expression in humans but triggers strong IFN-γ production

Akiko Kikuchi-Maki, Sei Ichi Yusa, Tracey L. Catina, Kerry S. Campbell

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

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 CD56high NK cells, although their expression was up-regulated by IL-2. Interestingly, Ab engagement of epitope-tagged 2DL4 triggered rapid and robust IFN-γ 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.

Original languageEnglish
Pages (from-to)3415-3425
Number of pages11
JournalJournal of Immunology
Volume171
Issue number7
DOIs
StatePublished - Oct 1 2003

Keywords

  • Adjuvants, Immunologic/biosynthesis
  • Amino Acid Motifs/physiology
  • Amino Acid Sequence
  • Cell Line
  • Cell Membrane/genetics
  • Cytoplasm/immunology
  • DNA Fragmentation/immunology
  • Down-Regulation/immunology
  • Genotype
  • Humans
  • Interferon-gamma/biosynthesis
  • Interleukin-2/pharmacology
  • Jurkat Cells
  • Killer Cells, Natural/immunology
  • Lymphocyte Activation/immunology
  • Molecular Sequence Data
  • Natural Cytotoxicity Triggering Receptor 2
  • Receptors, Immunologic/biosynthesis
  • Receptors, KIR
  • Receptors, KIR2DL4
  • Retroviridae/genetics
  • Transduction, Genetic
  • Tyrosine/metabolism
  • Up-Regulation/immunology
  • fas Receptor/physiology

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