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

AbstractFibrinogen‐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.

The FGL2‐FcγRIIB pathway: A novel mechanism leading to immunosuppression Journal Articles