Article: article from journal or magazin.
Impaired natural killing of MHC class I-deficient targets by NK cells expressing a catalytically inactive form of SHP-1.
Journal of immunology
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
NK cell function is negatively regulated by MHC class I-specific inhibitory receptors. Transduction of the inhibitory signal involves protein tyrosine phosphatases such as SHP-1 (SH2-containing protein tyrosine phosphatase-1). To investigate the role of SHP-1 for NK cell development and function, we generated mice expressing a catalytically inactive, dominant-negative mutant of SHP-1 (dnSHP-1). In this paper we show that expression of dnSHP-1 does not affect the generation of NK cells even though MHC receptor-mediated inhibition is partially impaired. Despite this defect, these NK cells do not kill syngeneic, normal target cells. In fact dnSHP-1-expressing NK cells are hyporesponsive toward MHC-deficient target cells, suggesting that non-MHC-specific NK cell activation is significantly reduced. In contrast, these NK cells mediate Ab-dependent cell-mediated cytotoxicity and prevent the engraftment with beta2-microglobulin-deficient bone marrow cells. A similar NK cell phenotype is observed in viable motheaten (mev) mice, which show reduced SHP-1 activity due to a mutation in the Shp-1 gene. In addition, NK cells in both mouse strains show a tendency to express more inhibitory MHC-specific Ly49 receptors. Our results demonstrate the importance of SHP-1 for the generation of functional NK cells, which are able to react efficiently to the absence of MHC class I molecules from normal target cells. Therefore, SHP-1 may play an as-yet-unrecognized role in some NK cell activation pathways. Alternatively, a reduced capacity to transduce SHP-1-dependent inhibitory signals during NK cell development may be compensated by the down-modulation of NK cell triggering pathways.
Animals, Antigens, Ly, Bone Marrow Transplantation/immunology, Catalysis, Cell Differentiation/genetics, Cell Differentiation/immunology, Cell Line, Crosses, Genetic, Cytotoxicity, Immunologic/genetics, Enzyme Activation/genetics, Enzyme Activation/immunology, Graft Rejection/genetics, Graft Rejection/immunology, Histocompatibility Antigens Class I/genetics, Immunity, Innate/genetics, Intracellular Signaling Peptides and Proteins, Killer Cells, Natural/cytology, Killer Cells, Natural/enzymology, Lectins, C-Type, Membrane Glycoproteins/physiology, Mice, Mice, Mutant Strains, Mice, Transgenic, Mutagenesis, Insertional, Point Mutation, Protein Phosphatase 1, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Protein Tyrosine Phosphatases/biosynthesis, Protein Tyrosine Phosphatases/deficiency, Receptors, NK Cell Lectin-Like, SH2 Domain-Containing Protein Tyrosine Phosphatases, T-Lymphocytes/cytology, Tumor Cells, Cultured, beta 2-Microglobulin/deficiency, beta 2-Microglobulin/genetics, src Homology Domains/genetics, src Homology Domains/immunology
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