Impaired Natural Killing of MHC Class I-Deficient Targets by NK Cells Expressing a Catalytically Inactive Form of SHP-1

Abstract

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 β2-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.

Ly49Q, a member of the Ly49 family that is selectively expressed on myeloid lineage cells and involved in regulation of cytoskeletal architecture

“…These results indicate that phosphorylation of the tyrosine residue in the ITIM is necessary for recruitment of SHP-1 and SHP-2 to Ly49Q. Thus, Ly49Q expressed on COS7 cells shows biochemical characteristics similar to other known Ly49 family members (12,(27)(28)(29).…”

Overexpression of interleukin‐15 in vivo enhances antitumor activity against mhc class I‐negative and ‐positive malignant melanoma through augmented NK activity and cytotoxic T‐cell response

“…Most of the mouse NK cells express MHC class I-inhibitory receptors such as Ly49 receptors, which contain tyrosine residues capable of binding to the SH2 domains of a tyrosine phosphatase, SHP-1 upon phosphorylation and counteract the kinase activity by recruiting SHP-1. 27,28,30 There are several lines of evidence indicating that MHC class I-deficient tumor cells are susceptible to NK cells. 31,32 Our results also showed that MHC class I-negative B16.44 melanoma cells are susceptible to the poly I:C-activated NK cells.…”

Soluble branched (1,4)‐β‐D‐glucans from Acetobacter species enhance antitumor activities against MHC class I‐negative and ‐positive malignant melanoma through augmented NK activity and cytotoxic T‐cell response

“…[25][26][27][28] On the other hand, MHC class I-deficient melanoma is not destroyed by cytotoxic CD8 þ T cells but is susceptible to NK cells, most of which express MHC class I-specific inhibitory receptors. [29][30][31][32] In the present study, we examined the effects of oral administration of AC-1 on protection against 2 murine B16 melanoma lines, MHC class I-negative B16L and MHC class I gene-transfected B16K b cells. Tumor growth was severely retarded in AC-1-treated mice after subcutaneous inoculation with B16L or B16K b cells.…”