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Science 306 (5701): 1517-1519

Copyright © 2004 by the American Association for the Advancement of Science

Natural Killer Cell Signaling Pathways

Eric Vivier,1* Jacques A. Nunès,2 Frédéric Vély3

Abstract: Natural killer (NK) cells are lymphocytes of the innate immune system that are involved in the early defenses against foreign cells, as well as autologous cells undergoing various forms of stress, such as microbial infection or tumor transformation. NK cell activation is controlled by a dynamic balance between complementary and antagonistic pathways that are initiated upon interaction with potential target cells. NK cells express an array of activating cell surface receptors that can trigger cytolytic programs, as well as cytokine or chemokine secretion. Some of these activating cell surface receptors initiate protein tyrosine kinase (PTK)–dependent pathways through noncovalent associations with transmembrane signaling adaptors that harbor intracytoplasmic ITAMs (immunoreceptor tyrosine-based activation motifs). Additional cell surface receptors that are not directly coupled to ITAMs also participate in NK cell activation. These include NKG2D, which is noncovalently associated to the DAP10 transmembrane signaling adaptor, as well as integrins and cytokine receptors. NK cells also express cell surface inhibitory receptors that antagonize activating pathways through protein tyrosine phosphatases (PTPs). These inhibitory cell surface receptors are characterized by intracytoplasmic ITIMs (immunoreceptor tyrosine-based inhibition motifs). The tyrosine-phosphorylation status of several signaling components that are substrates for both PTKs and PTPs is thus key to the propagation of the NK cell effector pathways. Understanding the integration of these multiple signals is central to the understanding and manipulation of NK cell effector signaling pathways.

1 Centre d'Immunologie de Marseille-Luminy, INSERM–CNRS–Univ. Méditerranée, Campus de Luminy, Case 906, 13288 Marseille cedex 09, France.
2 Institut de Cancérologie de Marseille, INSERM UMR 599, 13009 Marseille, France.
3 INSERM U608-Univ. Méditerranée, Faculté de Pharmacie, 13005 Marseille, France.

* To whom correspondence should be addressed. E-mail: vivier{at}

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Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci.
M. Carrington, S. Wang, M. P. Martin, X. Gao, M. Schiffman, J. Cheng, R. Herrero, A. C. Rodriguez, R. Kurman, R. Mortel, et al. (2005)
J. Exp. Med. 201, 1069-1075
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