Immunomodulation

The FGL2-FcγRIIB pathway: A novel mechanism leading to immunosuppression

  1. Hao Liu1,†,
  2. Itay Shalev1,†,
  3. Justin Manuel1,
  4. Wei He1,
  5. Elisa Leung2,
  6. Jennifer Crookshank1,
  7. Ming F. Liu1,
  8. Jun Diao1,
  9. Mark Cattral1,
  10. David A. Clark1,
  11. David E. Isenman2,
  12. Reginald M. Gorczynski1,3,
  13. David R. Grant1,3,
  14. Li Zhang1,4,
  15. Melville J. Phillips1,4,
  16. Myron I. Cybulsky1,4,
  17. Gary A. Levy1,5,*

Article first published online: 7 NOV 2008

DOI: 10.1002/eji.200838338

Issue

European Journal of Immunology

European Journal of Immunology

Volume 38, Issue 11, pages 3114–3126, November 2008

Additional Information

How to Cite

Liu, H., Shalev, I., Manuel, J., He, W., Leung, E., Crookshank, J., Liu, M. F., Diao, J., Cattral, M., Clark, D. A., Isenman, D. E., Gorczynski, R. M., Grant, D. R., Zhang, L., Phillips, M. J., Cybulsky, M. I. and Levy, G. A. (2008), The FGL2-FcγRIIB pathway: A novel mechanism leading to immunosuppression. Eur. J. Immunol., 38: 3114–3126. doi: 10.1002/eji.200838338

Author Information

  1. 1

    Multi-organ Transplant Program, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada

  2. 2

    Department of Biochemistry, University of Toronto, Toronto, ON, Canada

  3. 3

    Department of Surgery, University of Toronto, Toronto, ON, Canada

  4. 4

    Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

  5. 5

    Department of Medicine, University of Toronto, Toronto, ON, Canada

  1. †

    These authors contributed equally to this study.

*Toronto General Hospital, 585 University Ave., NCSB-11-1236, Toronto, ON, Canada M5G 2N2 Fax: +416-340-3378

Publication History

  1. Issue published online: 7 NOV 2008
  2. Article first published online: 7 NOV 2008
  3. Manuscript Accepted: 19 AUG 2008
  4. Manuscript Revised: 15 JUL 2008
  5. Manuscript Received: 14 MAR 2008

Funded by

  • Heart and Stroke Foundation of Canada. Grant Number: T5686
  • Canadian Institutes for Health Research. Grant Numbers: GR13298, 79561, STP 53882

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Keywords:

  • Fcγ receptors;
  • Fibrinogen-like protein;
  • Immunomodulation

Abstract

Fibrinogen-like protein 2 (FGL2) is a multifunctional protein, which has been implicated in the pathogenesis of allograft and xenograft rejection. Previously, FGL2 was shown to inhibit maturation of BM-derived DC and T-cell proliferation. The mechanism of the immunosuppressive activity of FGL2 remains poorly elucidated. Here, we focus on identification of FGL2-specific receptor(s) and their ability to modulate APC activity and allograft survival. Using flow cytometry and surface plasmon resonance analysis, we show that FGL2 binds specifically to Fc gamma receptor (FcγR)IIB and FcγRIII receptors, which are expressed on the surface of APC, including B lymphocytes, macrophages and DC. Antibody to FcγRIIB and FcγRIII, or deficiency of these receptors, abrogated FGL2 binding. FGL2 inhibited the maturation of BMDC from FcγRIIB+/+ mice but not from FcγRIIB−/− mice and induced apoptosis in the FcγRIIB+ mouse B-cell line (A20) but not the A20IIA1.6 cell line that does not express FcγRIIB. Recombinant FGL2 infused into FcγRIIB+/+ (C57BL/6J, H-2b) mice but not FcγRIIB−/− mice inhibited rejection of fully mismatched BALB/cJ (H-2d) skin allografts. The identification of specific receptor binding has important implications for the pathogenesis of immune-mediated disease and suggests a potential for targeted FGL2 therapy.

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