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

J Immunol. 2003 May 1;170(9):4539-47. doi: 10.4049/jimmunol.170.9.4539.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • SH2 Domain-Containing Protein Tyrosine Phosphatases
  • Sequence Deletion
  • Tumor Cells, Cultured
  • Tyrosine / genetics
  • src Homology Domains / genetics
  • src Homology Domains / immunology*

Substances

  • Adjuvants, Immunologic
  • Intracellular Signaling Peptides and Proteins
  • KIR3DL1 protein, human
  • Receptors, Immunologic
  • Receptors, KIR
  • Receptors, KIR3DL1
  • Tyrosine
  • Protein Phosphatase 2
  • PTPN11 protein, human
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases
  • Ptpn11 protein, mouse
  • Ptpn6 protein, mouse
  • SH2 Domain-Containing Protein Tyrosine Phosphatases