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Up on the tightrope: natural killer cell activation and inhibition

Abstract

Natural killer (NK) cells circulate through the blood, lymphatics and tissues, on patrol for the presence of transformed or pathogen-infected cells. As almost all NK cell receptors bind to host-encoded ligands, signals are constantly being transmitted into NK cells, whether they interact with normal or abnormal cells. The sophisticated repertoire of activating and inhibitory receptors that has evolved to regulate NK cell activity ensures that NK cells protect hosts against pathogens, yet prevents deleterious NK cell–driven autoimmune responses. Here I highlight recent advances in our understanding of the structural properties and signaling pathways of the inhibitory and activating NK cell receptors, with a particular focus on the ITAM-dependent activating receptors, the NKG2D-DAP10 receptor complexes and the CD244 receptor system.

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Figure 1: ITAM-containing NK receptors.
Figure 2: ITAM-mediated signaling in NK cells.
Figure 3: DAP10-mediated signaling in NK cells.
Figure 4: CD244 receptor complexes in NK cells.

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Acknowledgements

I thank D. Billadeau, A. Weiss, J. Djeu, J. Carlyle, C. Chang, J. Orange, S. Tangye and N. Bezman for discussions and help with the illustrations. Supported by the US National Institutes of Health (AI066897, AI068129, CA095137, CA105379 and AI64520) and the American Cancer Society. Dedicated to the memory of my friend Paul Leibson who made significant contributions to our understanding of NK cell receptor signaling.

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Correspondence to Lewis L Lanier.

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The University of California San Francisco has licensed intellectual property rights relating to NKG2D for potential therapeutic development.

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Lanier, L. Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9, 495–502 (2008). https://doi.org/10.1038/ni1581

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