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 language | English |
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Pages (from-to) | 3415-3425 |
Number of pages | 11 |
Journal | Journal of Immunology |
Volume | 171 |
Issue number | 7 |
DOIs | |
State | Published - 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