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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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.).
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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.
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Supplementary information
Supplementary Fig. 1
Specificity of polyclonal antibodies to FcγRIV. (PDF 32 kb)
Supplementary Fig. 2
Association of FcγRIV with FcRγ and enhancement of FcγRIV surface expression by FcRγ. (PDF 30 kb)
Supplementary Fig. 3
The 2.4G2 monoclonal antibody recognizes both FcγRIII and FcγRIV. (PDF 45 kb)
Supplementary Fig. 4
FcγRIV phosphorylation and association with Crk-L and PI3K. (PDF 23 kb)
Supplementary Fig. 5
Comparative analysis of the mouse and human Ig isotype-binding specificities for FcγRIII and FcγRIV. (PDF 75 kb)
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. (PDF 44 kb)
Supplementary Table 1
Comparison of FcγRIII and FcγRIV expression by different cell lines. (PDF 15 kb)
Supplementary Table 2
Ig binding affinities of FcγRIII and FcγRIV. (PDF 14 kb)
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Hirano, M., Davis, R., Fine, W. et al. IgEb immune complexes activate macrophages through FcγRIV binding. Nat Immunol 8, 762–771 (2007). https://doi.org/10.1038/ni1477
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DOI: https://doi.org/10.1038/ni1477
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