Src Homology Region 2-Containing Protein Tyrosine Phosphatase-2 (SHP-2) Can Play a Direct Role in the Inhibitory Function of Killer Cell Ig-Like Receptors in Human NK Cells

• Published in: The Journal of immunology (1950) 2003-05, Vol.170 (9), p.4539-4547
• Main Authors: Yusa, Sei-ichi, Campbell, Kerry S
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - biosynthesis; Adjuvants, Immunologic - genetics; Adjuvants, Immunologic - physiology; Amino Acid Motifs - genetics; Amino Acid Motifs - immunology; Amino Acid Sequence; Animals; Catalytic Domain - genetics; Catalytic Domain - immunology; Cell Line; Cytotoxicity Tests, Immunologic; Cytotoxicity, Immunologic - genetics; Cytotoxicity, Immunologic - immunology; Genetic Vectors; Humans; Intracellular Signaling Peptides and Proteins; Killer Cells, Natural - enzymology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; 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; Protein Tyrosine Phosphatases - genetics; Protein Tyrosine Phosphatases - physiology; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - genetics; Receptors, Immunologic - physiology; Receptors, KIR; Receptors, KIR3DL1; Sequence Deletion; SH2 Domain-Containing Protein Tyrosine Phosphatases; src Homology Domains - genetics; src Homology Domains - immunology; Tumor Cells, Cultured; Tyrosine - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.9.4539

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.