Sequential involvement of Lck and SHP-1 with MHC-recognizing receptors on NK cells inhibits FcR-initiated tyrosine kinase activation

Immunity. 1996 Dec;5(6):629-38. doi: 10.1016/s1074-7613(00)80276-9.

Abstract

Recognition of major histocompatibility (MHC) class I complexes on target cells by killer cell inhibitory receptors (KIR) blocks natural killer (NK) and T cell cytotoxic function. The inhibitory effect of KIR ligation requires the phosphotyrosine-dependent association of KIR with the cytoplasmic SH2-containing protein tyrosine phosphatase SHP-1. Using a somatic genetic model, we first define a requirement for the Src family protein tyrosine kinase (PTK) Lck in mediating KIR tyrosine phosphorylation. We then investigate how KIR ligation interrupts PTK-dependent NK cell activation signals. Specifically, we show that KIR ligation inhibits the Fc receptor (FcR)-induced tyrosine phosphorylation of the FcR-associated zeta signaling chain, the PTK ZAP-70, and phospholipase C gamma. Overexpression of catalytically inactive SHP-1 (acting as a dominant negative) restores the tyrosine phosphorylation of these signaling events and reverses KIR-mediated inhibition of NK cell cytotoxic function. These results suggest sequential roles for Lck and SHP-1 in the inhibition of PTK following MHC recognition by NK cells.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cytotoxicity, Immunologic*
  • GTP-Binding Proteins / metabolism
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immediate-Early Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Killer Cells, Natural / immunology*
  • Major Histocompatibility Complex
  • Mice
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins*
  • Phosphorylation
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Fc / metabolism
  • Receptors, Immunologic / metabolism*
  • Signal Transduction
  • Tyrosine / metabolism
  • src-Family Kinases / metabolism*

Substances

  • Histocompatibility Antigens Class I
  • Immediate-Early Proteins
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Fc
  • Receptors, Immunologic
  • Tyrosine
  • Protein-Tyrosine Kinases
  • src-Family Kinases
  • 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
  • GTP-Binding Proteins
  • GEM protein, human
  • Gem protein, mouse
  • Monomeric GTP-Binding Proteins