Article | Published:

IgEb immune complexes activate macrophages through FcγRIV binding

Nature Immunology volume 8, pages 762771 (2007) | Download Citation

Abstract

Because functional analysis of Fc receptors (FcRs) relies heavily on mouse models, the identification of another Fcγ receptor is particularly noteworthy. We demonstrate that FcγRIV, identified here as the mouse ortholog of primate FcγRIII, required association of the FcR γ-chain for optimal expression and function on myeloid cells; its signaling potential was also enhanced by a cytoplasmic 'YEEP' motif that was able to recruit the adaptor molecule Crk-L and phosphatidylinositol-3-OH kinase. Unexpectedly, FcγRIV 'preferentially' bound immunoglobulin E antibodies of the 'b' allotype (IgEb) as well as IgG2a and IgG2b antibodies. Ligation of FcγRIV by antigen-IgEb immune complexes promoted macrophage-mediated phagocytosis, presentation of antigen to T cells, production of proinflammatory cytokines and the late phase of cutaneous allergic reactions. IgEb antibody–mediated modification of macrophage responses may therefore influence mouse asthma models and strain-dependent differences in parasite susceptibility.

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GenBank/EMBL/DDBJ

Protein Data Bank

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Acknowledgements

We thank K. Maenaka and S. Nakae for discussions and suggestions; T. Kawakami, T. Kitamura, H. Tsutsui, K. Nakanishi, G.R.A. Ehrhardt, Z. Pancer, H. Kubagawa and J.F. Kearney for reagents or mice; G.L. Gartland, M. Hotomi, L.A. Gartland and Y. Kubagawa for technical assistance; and B.R. Herrin, M. Flurry, A. Brookshire and D. Lang for help in manuscript preparation. Supported by the National Institutes of Health (AI 39816; K08 award AI55638 to R.S.D.), the Charles A. Dana Foundation Program in Human Immunology (R.S.D.) and the Howard Hughes Medical Institute (M.H. and M.D.C.).

Author information

Affiliations

  1. Division of Developmental and Clinical Immunology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • Masayuki Hirano
    • , Randall S Davis
    • , W David Fine
    • , Robert P Stephan
    •  & Max D Cooper
  2. Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • Masayuki Hirano
    • , Randall S Davis
    • , Robert P Stephan
    •  & Max D Cooper
  3. Howard Hughes Medical Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • Masayuki Hirano
    • , W David Fine
    •  & Max D Cooper
  4. Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • Randall S Davis
  5. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • Randall S Davis
  6. Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • Randall S Davis
    •  & Max D Cooper
  7. Department of Biotechnology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.

    • Shugo Nakamura
    •  & Kentaro Shimizu
  8. Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan.

    • Hirokazu Yagi
    •  & Koichi Kato
  9. Departments of Pediatrics and Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.

    • Max D Cooper

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Contributions

M.H. designed and did experiments and prepared the manuscript; R.S.D. assisted in experimental design and manuscript preparation; W.D.F. did the surface plasmon resonance analysis; S.N. and K.S. did the structural analysis; H.Y. and K.K. did the glycosylation analysis; R.P.S. contributed to the PCR analysis; and M.D.C. contributed to the study design, data interpretation and manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Max D Cooper.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Specificity of polyclonal antibodies to FcγRIV.

  2. 2.

    Supplementary Fig. 2

    Association of FcγRIV with FcRγ and enhancement of FcγRIV surface expression by FcRγ.

  3. 3.

    Supplementary Fig. 3

    The 2.4G2 monoclonal antibody recognizes both FcγRIII and FcγRIV.

  4. 4.

    Supplementary Fig. 4

    FcγRIV phosphorylation and association with Crk-L and PI3K.

  5. 5.

    Supplementary Fig. 5

    Comparative analysis of the mouse and human Ig isotype-binding specificities for FcγRIII and FcγRIV.

  6. 6.

    Supplementary Fig. 6

    The peritoneal cavity cells from C57BL/6, BALB/c, Fcgr3−/−, or Fcer1g−/− mice were stained with anti-CD11b, anti-Gr-1, and anti-B220/CD45R.

  7. 7.

    Supplementary Table 1

    Comparison of FcγRIII and FcγRIV expression by different cell lines.

  8. 8.

    Supplementary Table 2

    Ig binding affinities of FcγRIII and FcγRIV.

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DOI

https://doi.org/10.1038/ni1477

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