Clonotypic differences in signaling from CD94 (kp43) on NK cells lead to 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 after ligation of the C-type lectin superfamily member, CD94. We isolated separate clonal populations of human NK cells in which ligation of CD94 (kp43) either triggered cell-mediated cytotoxicity (group A clones) or potently inhibited NK cell activation (group B clones). We then evaluated the proximal signaling events that regulate these alternative responses. CD94 stimulation of group A clones induced the rapid activation of intracellular protein tyrosine kinases (i.e., lck 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 instead inhibited the FcR-induced tyrosine phosphorylations of ZAP-70 and phospholipase C-gamma 2, the formation of phospho-zeta/ZAP-70 complexes, and the release of inositol phosphates. These results define distinct proximal signaling events initiated after CD94 ligation and suggest that clonotypic differences in signaling generate fundamentally different NK cell-mediated responses.
Brumbaugh
K M
KM
Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
Pérez-Villar
J J
JJ
Dick
C J
CJ
Schoon
R A
RA
López-Botet
M
M
Leibson
P J
PJ
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D002999:Clone Cells / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D004792:Enzyme Precursors / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D012515:Mast-Cell Sarcoma / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D051920:NK Cell Lectin-Like Receptor Subfamily D; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000502:physiology; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases / Q000502:physiology
D015703:Antigens, CD; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C497869:KLRD1 protein, human; C497870:Klrd1 protein, mouse; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D051920:NK Cell Lectin-Like Receptor Subfamily D; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D019061:src-Family Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma