The FGL2-FcgammaRIIB pathway: a novel mechanism leading to immunosuppression.
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 (FcgammaR)IIB and FcgammaRIII receptors, which are expressed on the surface of APC, including B lymphocytes, macrophages and DC. Antibody to FcgammaRIIB and FcgammaRIII, or deficiency of these receptors, abrogated FGL2 binding. FGL2 inhibited the maturation of BMDC from FcgammaRIIB+/+ mice but not from FcgammaRIIB(-/-) mice and induced apoptosis in the FcgammaRIIB+ mouse B-cell line (A20) but not the A20IIA1.6 cell line that does not express FcgammaRIIB. Recombinant FGL2 infused into FcgammaRIIB+/+ (C57BL/6J, H-2b) mice but not FcgammaRIIB(-/-) 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.
Liu
Hao
H
Multi-organ Transplant Program, Toronto General Research Institute, University Health Network, University of Toronto, Toronto, ON, Canada.
Shalev
Itay
I
Manuel
Justin
J
He
Wei
W
Leung
Elisa
E
Crookshank
Jennifer
J
Liu
Ming F
MF
Diao
Jun
J
Cattral
Mark
M
Clark
David A
DA
Isenman
David E
DE
Gorczynski
Reginald M
RM
Grant
David R
DR
Zhang
Li
L
Phillips
Melville J
MJ
Cybulsky
Myron I
MI
Levy
Gary A
GA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D005340:Fibrinogen / Q000502:physiology*; D006085:Graft Survival; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017452:Receptors, IgG / Q000502:physiology*; D016038:Skin Transplantation / Q000276:immunology; D014184:Transplantation, Homologous
C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; C490637:Fgl2 protein, mouse; D017452:Receptors, IgG; D005340:Fibrinogen