MOUSE LY-49A INTERRUPTS EARLY SIGNALING EVENTS IN NATURAL-KILLER-CELLCYTOTOXICITY AND FUNCTIONALLY ASSOCIATES WITH THE SHP-1 TYROSINE PHOSPHATASE

The lytic activity of natural killer (NK) cells is inhibited by the ex pression of class I major histocompatibility complex (MHC) antigens on target cells. In murine NK cells, Ly-49A mediates inhibition of cytot oxicity in response to the class I MHC antigen H-2D(d). In this report , we studied the function of mouse Ly-49A in both the rat NK cell tumo r line, RNK-16, transfected with Ly-49A cDNA, and in primary NK cells. We show that ligation of Ly-49A by H-2D(d) inhibits early signaling e vents during target cell stimulation, including polyphosphoinositide t urnover and tyrosine phosphorylation. We also show that Ly-49A directl y associates with the cytoplasmic tyrosine phosphatase SHP-1, and that Ly-49A function is impaired in NK cells from SHP-1 mutant viable moth eaten mice and from SHP-1-deficient motheaten mice. Finally, we demons trate that mutational substitution of the tyrosine within the proposed SHP-1 binding motif in Ly-49A completely abrogates inhibition of NK c ell cytotoxicity through this receptor. These results demonstrate that Ly-49A interrupts early activating signals in NK cells, and that SHP- 1 is an important mediator of Ly-49A function.