Multiplicity and plasticity of natural killer cell signaling pathways.
Natural killer (NK) cells express an array of activating receptors that associate with DAP12 (KARAP), CD3zeta, and/or FcRgamma ITAM (immunoreceptor tyrosine-based activation motif)-bearing signaling subunits. In T and mast cells, ITAM-dependent signals are integrated by critical scaffolding elements such as LAT (linker for activation of T cells) and NTAL (non-T-cell activation linker). Using mice that are deficient for ITAM-bearing molecules, LAT or NTAL, we show that NK cell cytotoxicity and interferon-gamma secretion are initiated by ITAM-dependent and -independent as well as LAT/NTAL-dependent and -independent pathways. The role of these various signaling circuits depends on the target cell as well as on the activation status of the NK cell. The multiplicity and the plasticity of the pathways that initiate NK cell effector functions contrast with the situation in T cells and B cells and provide an explanation for the resiliency of NK cell effector functions to various pharmacologic inhibitors and genetic mutations in signaling molecules.
Chiesa
Sabrina
S
Centre d'Immunologie de Marseille-Luminy, INSERM/CNRS, Université de la Méditerranée, Marseille Cedex 09, France.
Mingueneau
Michael
M
Fuseri
Nicolas
N
Malissen
Bernard
B
Raulet
David H
DH
Malissen
Marie
M
Vivier
Eric
E
Tomasello
Elena
E
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D003602:Cytotoxicity, Immunologic; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism* / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D010750:Phosphoproteins; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D007371:Interferon-gamma