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Fc receptor γ-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils

Abstract

The Fc receptor common γ-chain (FcRγ) is a widely expressed adaptor bearing an immunoreceptor tyrosine-based activation motif (ITAM) that transduces activation signals from various immunoreceptors. We show here that basophils lacking FcRγ developed normally and proliferated efficiently in response to interleukin 3 (IL-3) but were very impaired in IL-3-induced production of IL-4 and in supporting T helper type 2 differentiation. Through its transmembrane portion, FcRγ associated constitutively with the common β-chain of the IL-3 receptor and signaled by recruiting the kinase Syk. Retrovirus-mediated complementation demonstrated the essential function of the ITAM of FcRγ in IL-3 signal transduction. Our results identify a previously unknown mechanism whereby FcRγ functions to 'route' selective cytokine-triggered signals into the ITAM-mediated IL-4 production pathway.

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Figure 1: Normal development and proliferative responses to IL-3 of basophils in Fcer1g−/− mice.
Figure 2: Impaired IgE-independent, IL-3-induced production of IL-4 by FcRγ-deficient basophils.
Figure 3: Constitutive and functional association of FcRγ with βc in basophils.
Figure 4: Essential function for FcRγ ITAM in IL-3-induced IL-4 production.
Figure 5: Different requirements for transmembrane amino acids in FcRγ for IL-3 responses.
Figure 6: Different physical associations of FcRγ mutants with βc.
Figure 7: FcRγ-deficient basophils fail to support TH2 differentiation in vitro.

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Acknowledgements

We thank S. Akira (Osaka University) for Stat6−/− mice; W.R. Heath (Walter and Eliza Hall Institute) for OT-II TCR-Tg mice; T. Kitamura (University of Tokyo) for the original pMX-IRES-GFP retroviral vector; and K. Takatsu (University of Toyama) for the Y16 cell line; and acknowledge the late N. Azuta for technical assistance. Supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Japan Society for the Promotion of Science (Grants-in-Aid for Scientific Research 17047016, 18060016 to S.T. and 19591162 to S.H.).

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S.H. designed and did experiments and wrote the manuscript; S.Y. helped with vector construction and provided critical reagents; Y.S. did experiments; K.O., H.K., T.T. and T.S. provided critical reagents; M.T. and K.S. did the T. spiralis infection experiments; and S.T. designed and supervised research and wrote the manuscript.

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Correspondence to Shinsuke Taki.

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Hida, S., Yamasaki, S., Sakamoto, Y. et al. Fc receptor γ-chain, a constitutive component of the IL-3 receptor, is required for IL-3-induced IL-4 production in basophils. Nat Immunol 10, 214–222 (2009). https://doi.org/10.1038/ni.1686

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