Article | Published:

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

Nature Immunology volume 10, pages 214222 (2009) | Download Citation

Subjects

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Cytokine pleiotropy and redundancy: a view from the receptor. Stem Cells 12 Suppl 1, 3–12 (1994).

  2. 2.

    et al. The interleukin-2 receptor γ chain: its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu. Rev. Immunol. 14, 179–205 (1996).

  3. 3.

    Cytokine signaling through nonreceptor protein tyrosine kinases. Science 268, 251–255 (1995).

  4. 4.

    & Gp130 and the interleukin-6 family of cytokines. Annu. Rev. Immunol. 15, 797–819 (1997).

  5. 5.

    , & Specificity in cytokine signal transduction: lessons learned from the IL-3/IL-5/GM-CSF receptor family. Cytokine Growth Factor Rev. 12, 19–25 (2001).

  6. 6.

    , , , & Cytokine receptors and signal transduction. Annu. Rev. Immunol. 10, 295–331 (1992).

  7. 7.

    Interleukin 5 and B cell differentiation. Cytokine Growth Factor Rev. 9, 25–35 (1998).

  8. 8.

    et al. Granulocyte-macrophage colony-stimulating factor regulates effector differentiation of invariant natural killer T cells during thymic ontogeny. Immunity 25, 487–497 (2006).

  9. 9.

    , & The human basophil: a new appreciation of its role in immune responses. Blood 96, 4028–4038 (2000).

  10. 10.

    et al. Stimulation of proliferation, differentiation, and function of human cells by primate interleukin 3. Proc. Natl. Acad. Sci. USA 84, 2761–2765 (1987).

  11. 11.

    , , & IL-3 signaling and the role of Src kinases, JAKs and STATs: a covert liaison unveiled. Oncogene 19, 2532–2547 (2000).

  12. 12.

    , , , & Requirement of Lyn and Syk tyrosine kinases for the prevention of apoptosis by cytokines in human eosinophils. J. Exp. Med. 183, 1407–1414 (1996).

  13. 13.

    , , , & The intracellular signal transduction mechanism of interleukin 5 in eosinophils: the involvement of lyn tyrosine kinase and the Ras-Raf-1- MEK-microtubule-associated protein kinase pathway. J. Exp. Med. 181, 1827–1834 (1995).

  14. 14.

    , , , & Syk-deficient eosinophils show normal interleukin-5-mediated differentiation, maturation, and survival but no longer respond to FcγR activation. Blood 96, 2506–2510 (2000).

  15. 15.

    & Regulation of antigen receptor signal transduction by protein tyrosine kinases. Curr. Opin. Immunol. 8, 394–401 (1996).

  16. 16.

    , & ITAM-based signaling beyond the adaptive immune response. Immunol. Lett. 104, 29–37 (2006).

  17. 17.

    et al. Interleukin-3 activates Syk in a human myeloblastic leukemia cell line, AML193. Eur. J. Biochem. 249, 792–796 (1997).

  18. 18.

    , & The 21st century renaissance of the basophil? Current insights into its role in allergic responses and innate immunity. Exp. Dermatol. 15, 855–864 (2006).

  19. 19.

    , , & Induction of Th2 type immunity in a mouse system reveals a novel immunoregulatory role of basophils. Blood 109, 2921–2927 (2007).

  20. 20.

    , , & Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood 106, 2011–2017 (2005).

  21. 21.

    , , & A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat. Immunol. 9, 310–318 (2008).

  22. 22.

    et al. Cutting edge: IPSE/alpha-1, a glycoprotein from Schistosoma mansoni eggs, induces IgE-dependent, antigen-independent IL-4 production by murine basophils in vivo. J. Immunol. 178, 6023–6027 (2007).

  23. 23.

    , , , & A two-step process for cytokine production revealed by IL-4 dual-reporter mice. Immunity 23, 419–429 (2005).

  24. 24.

    et al. Resistance of Fc receptor-deficient mice to fatal glomerulonephritis. J. Clin. Invest. 102, 1229–1238 (1998).

  25. 25.

    et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J. Exp. Med. 200, 507–517 (2004).

  26. 26.

    et al. Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity 23, 191–202 (2005).

  27. 27.

    et al. Essential role of Stat6 in IL-4 signalling. Nature 380, 627–630 (1996).

  28. 28.

    et al. IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils. Proc. Natl. Acad. Sci. USA 96, 13962–13966 (1999).

  29. 29.

    et al. Basophils enhance immunological memory responses. Nat. Immunol. 9, 733–742 (2008).

  30. 30.

    et al. Mast cells and basophils are selectively activated in vitro and in vivo through CD200R3 in an IgE-independent manner. J. Immunol. 179, 7093–7100 (2007).

  31. 31.

    et al. Molecular characterization of the β chain of the murine interleukin 5 receptor. Int. Immunol. 3, 665–672 (1991).

  32. 32.

    et al. FcεRIγ-ITAM Is differentially required for mast cell function in vivo. J. Immunol. 172, 2374–2381 (2004).

  33. 33.

    , , & A common site of the Fc receptor γ subunit interacts with the unrelated immunoreceptors FcαRI and FcεRI. J. Biol. Chem. 281, 17108–17113 (2006).

  34. 34.

    & Control of infection with Leishmania major in susceptible BALB/c mice lacking the common γ-chain for FcR is associated with reduced production of IL-10 and TGF-β by parasitized cells. J. Immunol. 174, 6340–6345 (2005).

  35. 35.

    et al. Critical role of the Fc receptor γ-chain on APCs in the development of allergen-induced airway hyperresponsiveness and inflammation. J. Immunol. 178, 480–488 (2007).

  36. 36.

    et al. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol. Rev. 201, 139–155 (2004).

  37. 37.

    et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005).

  38. 38.

    et al. Amplification of IFN-α-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nat. Immunol. 5, 1181–1189 (2004).

  39. 39.

    et al. Integrin signaling in neutrophils and macrophages uses adaptors containing immunoreceptor tyrosine-based activation motifs. Nat. Immunol. 7, 1326–1333 (2006).

  40. 40.

    , , , & Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. Immunity 22, 427–438 (2005).

  41. 41.

    et al. Alternative endocytic pathway for immunoglobulin A Fc receptors (CD89) depends on the lack of FcRγ association and protects against degradation of bound ligand. J. Biol. Chem. 274, 7216–7225 (1999).

  42. 42.

    , , & Colostral neutrophils express Fcα receptors (CD89) lacking γ chain association and mediate noninflammatory properties of secretory IgA. J. Leukoc. Biol. 69, 289–296 (2001).

  43. 43.

    et al. Functional inactivation in mice of the gene for the interleukin-3 (IL- 3)-specific receptor β-chain: implications for IL-3 function and the mechanism of receptor transmodulation in hematopoietic cells. Blood 87, 2665–2674 (1996).

  44. 44.

    & Basophils and type 2 immunity. Curr. Opin. Hematol. 15, 59–63 (2008).

  45. 45.

    , , & Toll-like receptor 2 ligands activate human basophils for both IgE-dependent and IgE-independent secretion. J. Allergy Clin. Immunol. 115, 295–301 (2005).

  46. 46.

    , , & Basophils express a type 2 cytokine profile on exposure to proteases from helminths and house dust mites. J. Leukoc. Biol. 73, 165–171 (2003).

  47. 47.

    et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763 (2004).

  48. 48.

    et al. Protein-tyrosine kinase Syk is required for pathogen engulfment in complement-mediated phagocytosis. Blood 107, 4554–4562 (2006).

  49. 49.

    , & Bisphenol A promotes IL-4 production by Th2 cells. Int. Arch. Allergy Immunol. 132, 240–247 (2003).

Download references

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.).

Author information

Affiliations

  1. Department of Immunology and Infectious Diseases, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan.

    • Shigeaki Hida
    • , Yuzuru Sakamoto
    • , Masaya Takamoto
    • , Kazuo Sugane
    •  & Shinsuke Taki
  2. Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan.

    • Sho Yamasaki
    •  & Takashi Saito
  3. Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo 113-8519, Japan.

    • Kazushige Obata
    •  & Hajime Karasuyama
  4. Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.

    • Toshiyuki Takai

Authors

  1. Search for Shigeaki Hida in:

  2. Search for Sho Yamasaki in:

  3. Search for Yuzuru Sakamoto in:

  4. Search for Masaya Takamoto in:

  5. Search for Kazushige Obata in:

  6. Search for Toshiyuki Takai in:

  7. Search for Hajime Karasuyama in:

  8. Search for Kazuo Sugane in:

  9. Search for Takashi Saito in:

  10. Search for Shinsuke Taki in:

Contributions

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.

Corresponding author

Correspondence to Shinsuke Taki.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–12 and Supplementary Methods

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.1686

Further reading