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

Sei Ichi Yusa, Kerry S. Campbell

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

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 languageEnglish
Pages (from-to)4539-4547
Number of pages9
JournalJournal of Immunology
Volume170
Issue number9
DOIs
StatePublished - 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

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