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An essential function for β-arrestin 2 in the inhibitory signaling of natural killer cells

Abstract

The inhibitory signaling of natural killer (NK) cells is crucial in the regulation of innate immune responses. Here we show that the association of KIR2DL1, an inhibitory receptor of NK cells, with β-arrestin 2 mediated recruitment of the tyrosine phosphatases SHP-1 and SHP-2 to KIR2DL1 and facilitated 'downstream' inhibitory signaling. Consequently, the cytotoxicity of NK cells was higher in β-arrestin 2–deficient mice but was inhibited in β-arrestin 2–transgenic mice. Moreover, β-arrestin 2–deficient mice were less susceptible than wild-type mice to mouse cytomegalovirus infection, an effect that was abolished by depletion of NK cells. Our findings identify a previously unknown mechanism by which the inhibitory signaling in NK cells is regulated.

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Figure 1: Interaction of β-arrestin 2 with KIR2DL1.
Figure 2: Receptor–stimulated interaction of β-arrestin 2 with KIR2DL1.
Figure 3: ITIM phosphorylation–dependent interaction of KIR2DL1 with β-arrestin 2.
Figure 4: Regulation of KIR2DL1-mediated inhibition of cytotoxicity by β-arrestin 2.
Figure 5: Regulation of KIR2DL1 signaling by β-arrestin 2.
Figure 6: The recruitment of SHP-1 or SHP-2 to KIR2DL is facilitated by β-arrestin 2.
Figure 7: Regulation of NK cell cytotoxicity by β-arrestin 2 in vivo.

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Acknowledgements

We thank E.O. Long, E. Vivier, D.M. Davis, C. Dong and S.M. Skinner for critical reading of the manuscript; R.J. Lefkowitz (Duke University Medical Center) for β-arrestin 2–deficient mice and rabbit polyclonal anti–β-arrestin 2; Z. Chen (Wuhan Institute of Virology, Chinese Academy of Sciences) for MCMV; H. Gu (Beth Israel Deaconess Medical Center) for SHP-1and SHP-2 constructs; and J.-J. Cai for technical assistance. Supported by the Ministry of Science and Technology (2006CB 504300), the National Natural Science Foundation of China (projects 30321002 and 30471580), Shanghai E-research Institutes and Science and Technology Commission of Shanghai Municipality (projects 04DZ14902 and 07pj14096).

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M.-C.Y. designed and did most experiments, analyzed data and prepared the manuscript; L.-L.S., L.Z., Y.L. and N.W. did the experiments; L.K., Z.-H.Z., L.S., H.-P.L. and J.-H.H. assisted with experiments; D.L. prepared the manuscript; J.L.S. provided materials. J.-W.Z. and G.P. designed the experiments; and B.-X.G. conceptualized the research, directed the study and prepared the manuscript.

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Correspondence to Gang Pei or Bao-Xue Ge.

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Yu, MC., Su, LL., Zou, L. et al. An essential function for β-arrestin 2 in the inhibitory signaling of natural killer cells. Nat Immunol 9, 898–907 (2008). https://doi.org/10.1038/ni.1635

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