SEQUENTIAL INVOLVEMENT OF LCK AND SHP-1 WITH MHC-RECOGNIZING RECEPTORS ON NK CELLS INHIBITS FCR-INITIATED TYROSINE KINASE ACTIVATION

Recognition of major histocompatibility (MHC) class I complexes on tar get cells by killer cell inhibitory receptors (KIR) blocks natural kil ler (NK) and T cell cytotoxic function. The inhibitory effect of KIR l igation requires the phosphotyrosine-dependent association of KIR with the cytoplasmic SH2-containing protein tyrosine phosphatase SHP-1. Us ing a somatic genetic model, we first define a requirement for the Src family protein tyrosine kinase (PTK) Lck in mediating KIR tyrosine ph osphorylation. We then investigate how KIR ligation interrupts PTK-dep endent NK cell activation signals, Specifically, we show that KIR liga tion inhibits the Fc receptor (FcR)-induced tyrosine phosphorylation o f the FcR-associated zeta signaling chain, the PTK ZAP-70, and phospho lipase C gamma. Overexpression of catalytically inactive SHP-1 (acting as a dominant negative) restores the tyrosine phosphorylation of thes e signaling events and reverses KIR-mediated inhibition of NK cell cyt otoxic function, These results suggest sequential roles for Lck and SH P-1 in the inhibition of PTK following MHC recognition by NK cells.