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)-1, 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adjuvants, Immunologic / biosynthesis
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / physiology*
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Amino Acid Motifs / genetics
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Amino Acid Motifs / immunology
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Amino Acid Sequence
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Animals
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Catalytic Domain / genetics
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Catalytic Domain / immunology
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Cell Line
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Cytotoxicity Tests, Immunologic
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Cytotoxicity, Immunologic / genetics
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Cytotoxicity, Immunologic / immunology
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Genetic Vectors
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Humans
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Intracellular Signaling Peptides and Proteins
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Killer Cells, Natural / enzymology*
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Killer Cells, Natural / immunology*
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Killer Cells, Natural / metabolism
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Mice
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Molecular Sequence Data
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Mutagenesis, Site-Directed
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Protein Phosphatase 2
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases / biosynthesis
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Protein Tyrosine Phosphatases / genetics
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Protein Tyrosine Phosphatases / physiology*
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Receptors, Immunologic / antagonists & inhibitors
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology*
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Receptors, KIR
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Receptors, KIR3DL1
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SH2 Domain-Containing Protein Tyrosine Phosphatases
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Sequence Deletion
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Tumor Cells, Cultured
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Tyrosine / genetics
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src Homology Domains / genetics
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src Homology Domains / immunology*
Substances
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Adjuvants, Immunologic
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Intracellular Signaling Peptides and Proteins
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KIR3DL1 protein, human
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Receptors, Immunologic
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Receptors, KIR
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Receptors, KIR3DL1
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Tyrosine
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Protein Phosphatase 2
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PTPN11 protein, human
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Protein Tyrosine Phosphatases
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Ptpn11 protein, mouse
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Ptpn6 protein, mouse
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SH2 Domain-Containing Protein Tyrosine Phosphatases