NKG2D triggers cytotoxicity in mouse NK cells lacking DAP12 or Syk family kinases.
In activated mouse natural killer (NK) cells, the NKG2D receptor associates with two intracellular adaptors, DAP10 and DAP12, which trigger phosphatidyl inositol 3 kinase (PI3K) and Syk family protein tyrosine kinases, respectively. Here we show that cytotoxicity, but not cytokine production, is triggered by NKG2D in activated NK cells lacking either DAP12 or the Syk family members Syk and ZAP70. Inhibition of PI3K blocks this cytotoxicity, suggesting that the DAP10-PI3K pathway is sufficient to initiate NKG2D-mediated killing of target cells. Our results highlight signaling divergence in the effector functions of NKG2D and indicate that alternative associations between a receptor and its adaptors may provide a single receptor with a dual 'on-switch', giving mouse NK cells more choices through which to trigger cytotoxicity.
Department of Immunology, Pasteur Institute, 25-28 rue Dr Roux, 75015 Paris, France.
Simona
S
Zompi
Jessica A
JA
Hamerman
Kouetsu
K
Ogasawara
Edina
E
Schweighoffer
Victor L J
VL
Tybulewicz
James P
JP
Di Santo
Lewis L
LL
Lanier
Francesco
F
Colucci
D000818:Animals; D003602:Cytotoxicity, Immunologic; D004792:Enzyme Precursors / Q000276:immunology*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000276:immunology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D014407:Tumor Cells, Cultured; D051746:ZAP-70 Protein-Tyrosine Kinase
D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C527086:Klrk1 protein, mouse; C000606897:Syk protein, mouse; C497262:Zap70 protein, mouse