Abstract
The inhibitory forms of killer cell Ig-like receptors (KIR) are MHC class I-binding receptors that are expressed by human NK cells and prevent their attack of normal cells. Substantial evidence indicates that the mechanism of KIR-mediated inhibition involves recruitment of the protein tyrosine phosphatase, Src homology region 2-containing protein tyrosine phosphatase (SHP)-I, to phosphorylated immunoreceptor tyrosine-based inhibitory motifs (ITIMs). However, the functional significance of parallel recruitment of a SHP-1-related phosphatase, SHP-2, to KIR ITIMs has not been addressed. In the present study, our results with mutant forms of a classical KIR, KIR3DL1, show a direct correlation between SHP-2 recruitment and functional inhibition of target cell conjugation and cytotoxicity. In addition, KIR3DL1 inhibition of target cell cytotoxicity is blocked by overexpression of a dominant-negative form of SHP-2. Finally, KIR3DL1 fused directly with the catalytic domain of SHP-2 inhibits both target cell conjugation and cytotoxicity responses. These results strongly indicate that SHP-2 catalytic activity plays a direct role in inhibitory KIR functions, and SHP-2 inhibits NK cell activation in concert with SHP-1.
Original language | English |
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Pages (from-to) | 4539-4547 |
Number of pages | 9 |
Journal | Journal of Immunology |
Volume | 170 |
Issue number | 9 |
DOIs | |
State | Published - May 1 2003 |
Keywords
- Adjuvants, Immunologic/biosynthesis
- Amino Acid Motifs/genetics
- Amino Acid Sequence
- Animals
- Catalytic Domain/genetics
- Cell Line
- Cytotoxicity Tests, Immunologic
- Cytotoxicity, Immunologic/genetics
- Genetic Vectors
- Humans
- Intracellular Signaling Peptides and Proteins
- Killer Cells, Natural/enzymology
- Mice
- Molecular Sequence Data
- Mutagenesis, Site-Directed
- Protein Phosphatase 2
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
- Protein Tyrosine Phosphatases/biosynthesis
- Receptors, Immunologic/antagonists & inhibitors
- Receptors, KIR
- Receptors, KIR3DL1
- SH2 Domain-Containing Protein Tyrosine Phosphatases
- Sequence Deletion
- Tumor Cells, Cultured
- Tyrosine/genetics
- src Homology Domains/genetics