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Nature Immunology 9, 898–907 (1 August 2008) | doi:10.1038/ni.1635

An essential function for |[beta]|-arrestin 2 in the inhibitory signaling of natural killer cells

Ming-Can Yu , Liu-Li Su , Lin Zou , Ye Liu , Na Wu , Ling Kong , Zi-Heng Zhuang , Lei Sun , Hai-Peng Liu , Jun-Hao Hu , Dangsheng Li , Jack L Strominger , Jing-Wu Zang , Gang Pei & Bao-Xue Ge

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.