INHIBITION OF SELECTIVE SIGNALING EVENTS IN NATURAL-KILLER-CELLS RECOGNIZING MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I

Many studies have characterized the transmembrane signaling events ini tiated after T-cell antigen receptor recognition of major histocompati bility complex (MHC)-bound peptides, Yet, little is known about signal transduction from a set of MHC class I recognizing receptors on natur al killer (NK) cells whose ligation dramatically inhibits NK cell-medi ated killing. In this study we evaluated the influence of MHC recognit ion on the proximal signaling events in NK cells binding tumor targets . We utilized two experimental models where NK cell-mediated cytotoxic ity was fully inhibited by the recognition of specific MHC class I mol ecules, NK cell binding to either class I-deficient or class I-transfe cted target cells initiated rapid protein tyrosine kinase activation, In contrast, whereas NR cell binding to class I-deficient targets led to inositol phosphate release and increased intracellular free calcium ([Ca2+](i)), NK recognition of class I-bearing targets did not induce the activation of these phospholipase C-dependent signaling events, T he recognition of class I by NK cells clearly had a negative regulator y effect since blocking this interaction using anti-class I F(ab')(2) fragments increased inositol 1,4,5-trisphosphate release and [Ca2+](i) and increased the lysis of the targets. These results suggest that on e of the mechanisms by which NK cell recognition of specific MHC class I molecules can block the development of cell-mediated cytotoxicity i s by inhibiting specific critical signaling events.