CLONOTYPIC DIFFERENCES IN SIGNALING FROM CD94 (KP43) ON NK CELLS LEADTO DIVERGENT CELLULAR-RESPONSES

Ligation of MHC class I-recognizing receptors on NK cells dramatically modulates their secretory and cytotoxic function, This study focuses on characterizing key signaling events regulating these activities aft er ligation of the C-type lectin superfamily member, CD94, We isolated separate clonal populations of human NK cells in which ligation of CD 94 (kp43) either triggered cell-mediated cytotoxicity (group A clones) or potently inhibited NK cell activation (group B clones), We then ev aluated the proximal signaling events that regulate these alternative responses, CD94 stimulation of group A clones induced the rapid activa tion of intracellular protein tyrosine kinases (i,e., Ick and ZAP-70), phospholipase C, and phosphatidylinositol 3-kinase, In contrast, CD94 ligation on group B clones had none of the above noted effects and in stead inhibited the FcR-induced tyrosine phosphorylations of ZAP-70 an d phospholipase C-gamma 2, the formation of phospho-zeta/ZAP-70 comple xes and the release of inositol phosphates, These results define disti nct proximal signaling events initiated after CD94 ligation and sugges t that clonotypic differences in signaling generate fundamentally diff erent NK cell-mediated responses.