The FGL2-FcγRIIB 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 (Fc gamma R)IIB and Fc gamma RIII receptors, which are expressed on the surface of APC, including B lymphocytes, macrophages and DC. Antibody to Fc gamma RIIB and Fc gamma RIII, or deficiency of these receptors, abrogated FGL2 binding. FGL2 inhibited the maturation of BMDC from Fc gamma RIIB+/+ mice but not from Fc gamma RIIB-/- mice and induced apoptosis in the Fc gamma RIIB+ mouse B-cell line (A20) but not the A20IIA1.6 cell line that does not express Fc gamma RIIB. Recombinant FGL2 infused into Fc gamma RIIB+/+ (C57BL/6J, H-2(b)) mice but not Fc gamma RIIB-/- mice inhibited rejection of fully mismatched BALB/cJ (H-2(d)) 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.