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