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 muta nt of SHP-1 (dnSHP-1), In this paper we show that expression of dnSHP-1 doe s not affect the generation of NK cells even though MHC receptor-mediated i nhibition is partially impaired. Despite this defect, these NK cells do not hill syngeneic, normal target cells. In fact dnSHP-1-expressing NK cells a re hyporesponsive toward MHC-deficient target cells, suggesting that non-MH C-specific NK cell activation is significantly reduced. In contrast, these NK cells mediate Ab-dependent cell-mediated cytotoxicity and prevent the en graftment with beta(2)-microglobulin-deficient bone marrow cells. A similar NK cell phenotype is observed in viable motheaten (me(nu)) mice, which sho w 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 M HC-specific Ly49 receptors, Our results demonstrate the importance of SHP-1 for the generation of functional NK cells, which are able to react efficie ntly to the absence of MHC class I molecules from normal target cells. Ther efore, SHP-1 may play an as-yet-unrecognized role in some NK cell activatio n pathways. Alternatively, a reduced capacity to transduce SHP-1-dependent inhibitory signals during NK cell development may be compensated by the dow n modulation of NK fell triggering pathways.