Abstract
Recognition of major histocompatibility (MHC) class I complexes on target cells by killer cell inhibitory receptors (KIR) blocks natural killer (NK) and T cell cytotoxic function. The inhibitory effect of KIR ligation requires the phosphotyrosine-dependent association of KIR with the cytoplasmic SH2-containing protein tyrosine phosphatase SHP-1. Using a somatic genetic model, we first define a requirement for the Src family protein tyrosine kinase (PTK) Lck in mediating KIR tyrosine phosphorylation. We then investigate how KIR ligation interrupts PTK-dependent NK cell activation signals. Specifically, we show that KIR ligation inhibits the Fc receptor (FcR)-induced tyrosine phosphorylation of the FcR-associated ζ signaling chain, the PTK ZAP-70, and phospholipase Cγ. Overexpression of catalytically inactive SHP-1 (acting as a dominant negative) restores the tyrosine phosphorylation of these signaling events and reverses KIR-mediated inhibition of NK cell cytotoxic function. These results suggest sequential roles for Lck and SHP-1 in the inhibition of PTK following MHC recognition by NK cells.
Original language | English (US) |
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Pages (from-to) | 629-638 |
Number of pages | 10 |
Journal | Immunity |
Volume | 5 |
Issue number | 6 |
DOIs | |
State | Published - Dec 1996 |
Bibliographical note
Funding Information:Correspondence should be addressed to P. J. L. This research was supported by the Mayo Foundation and by National Institutes of Health grants CA47752 and GM47286.