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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2364-2372.
Prepublished online as a Blood First Edition Paper on November 15, 2005; DOI 10.1182/blood-2005-08-3504.
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Submitted August 30, 2005
Accepted October 24, 2005
Multiplicity and plasticity of Natural Killer cell signaling pathways
Sabrina Chiesa, Michael Mingueneau, Nicolas Fuseri, Bernard Malissen, David H Raulet, Marie Malissen, Eric Vivier*, and Elena Tomasello
Centre d'Immunologie de Marseille-Luminy, INSERM - CNRS - Universite de la Mediterranee, Marseille, France
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA
* Corresponding author; email: vivier{at}ciml.univ-mrs.fr.
Natural Killer (NK) cells express an array of activating receptors that associate with DAP12 (KARAP), CD3 and/or FcR 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- 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 pharmacological inhibitors and genetic mutations in signaling molecules.
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