Overexpression of fibrinogen-like protein 2 protects against T cell-induced colitis

Abstract

AIMTo determine the effect of overexpression of fibrinogen-like protein 2 (FGL2) on regulatory T cell (Treg) and effector T (Teff) cell function on T cell-induced colitis in Rag1-/- mice.METHODSTreg and Teff cells from fgl2-/-, fgl2+/+, and fgl2Tg mice were purified by FACS. They were studied in vitro for immunosuppressive activity and cell proliferation and in vivo for their effects on the development and prevention of T cell-induced colitis in Rag1-/- mice.RESULTSIn vitro, fgl2Tg Treg had enhanced immunosuppressive activity, and fgl2Tg Teff had reduced proliferation to alloantigen stimulation. Transfer of Teff from C57Bl/6J mice (fgl2+/+) into Rag1-/- mice produced both clinical and histologic colitis with dense infiltrates of CD3+ T cells, crypt abscesses and loss of goblet cells. Fgl2Tg Treg prevented the development of T cell-induced colitis, whereas fgl2+/+ and fgl2-/- Treg were only partially protective. In mice that received fgl2Tg Treg, the ratio of Foxp3+ to CD3+ cells was increased both in the colon and in mesenteric lymph nodes, and Teff cell proliferation as determined by staining with Ki67 was reduced. Teff cells from fgl2Tg mice did not produce colitis.CONCLUSIONHere we show that fgl2Tg Teff are hypoproliferative and do not induce colitis. We further demonstrate that fgl2Tg Treg prevent colitis in contrast to fgl2+/+ Treg, which were only partially protective. These studies collectively provide a rationale for exploring the use of FGL2 or Treg expressing high levels of FGL2 in the treatment of inflammatory bowel disease.

Soluble fibrinogen-like protein 2 promotes the growth of hepatocellular carcinoma via attenuating dendritic cell-mediated cytotoxic T cell activity

“…Soluble FGL2 (sFGL2) is an immunosuppressive factor that inhibits dendritic cells (DCs) [10] by binding to the FcγRIIB receptor [11]. As an immune regulator, sFGL2 plays a critical role in the immune balance in autoimmune diseases and can restrict the progression of autoimmune glomerulonephritis [12] and T cell-induced colitis [13]. However, in viral hepatitis, sFGL2 attenuates antiviral immunity, leading to poor prognosis, with impaired Treg function and prolonged survival time observed following FGL2 blockage in murine models of viral fulminant hepatitis [14].…”

Control of Intestinal Inflammation, Colitis-Associated Tumorigenesis, and Macrophage Polarization by Fibrinogen-Like Protein 2

“…To date, experimental evidence is still lacking to address which cell type drives Fgl2 expression in intestinal inflammation, we found that colonic macrophages are the major source of both mFgl2 and sFgl2 in colitis. A recent report implied that Tregs and effector T cells control intestinal homeostasis through expression of Fgl2 in a T cell-induced colitis model ( 29 ). Similarly, we propose here that in the context of inflammation, colonic macrophages may through express Fgl2 partially restore intestinal homeostasis.…”

Inhibition of the Fibrinogen‐Like Protein 2:FcγRIIB/RIII immunosuppressive pathway enhances antiviral T‐cell and B‐cell responses leading to clearance of lymphocytic choriomeningitis virus clone 13

“…Although we have reported that Treg cells are a major source of FGL2, other cells including macrophages and CD8 + T cells can produce FGL2. Hence at this time we cannot unequivocally state that increased FGL2 in the plasma is solely due to production by Treg . We used mice that were genetically deficient in fgl2 to study the effects of FGL2 on both the innate and adaptive antiviral immune response.…”

“…Hence at this time we cannot unequivocally state that increased FGL2 in the plasma is solely due to production by Treg. 22,51,52 We used mice that were genetically deficient in fgl2 to study the effects of FGL2 on both the innate and adaptive antiviral immune response. Post LCMV cl-13 infection, fgl2 À/À mice had increased numbers of macrophages and DC that expressed CD80, CD86 and MHC-II, markers of macrophage and DC activation in comparison with fgl2 +/+ mice.…”