Impaired natural killing of MHC class I-deficient targets by NK cells expressing a catalytically inactive form of SHP-1.
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.
Lowin-Kropf
B
B
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
Kunz
B
B
Beermann
F
F
Held
W
W
D000818:Animals; D000950:Antigens, Ly; D016026:Bone Marrow Transplantation / Q000276:immunology; D002384:Catalysis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D017354:Point Mutation; D054645:Protein Phosphatase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D055630:Receptors, NK Cell Lectin-Like; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D013601:T-Lymphocytes / Q000166:cytology; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; D047908:Intracellular Signaling Peptides and Proteins; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055630:Receptors, NK Cell Lectin-Like; D001613:beta 2-Microglobulin; D054645:Protein Phosphatase 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases