Fibrinogen-like protein 2, also known as FGL2, is a protein which in humans is encoded by the FGL2 gene. Structure FGL2 is a 439 amino acid secreted protein that is similar to the β- and γ-chains of fibrinogen. The carboxyl-terminus of the encoded protein consists of the fibrinogen-related domains (FRED). The encoded protein forms a tetrameric complex which is stabilized by interchain disulfide bonds. Function This protein may play a role in physiologic functions at mucosal sites. FGL2 is a protein that exhibits pleiotropic effects within the body and is an important immune regulator of both innate and adaptive responses. The protein exists as both a Type II transmembrane protein (with the carboxy terminus on the extracellular side of the plasma membrane) found on the surface of macrophages and endothelial cells and can be constitutively secreted by both CD4+ and CD8+ T cells. Variants Membrane bound Membrane bound FGL2 (mFGL2) exhibits a prothrombinase activity, resulting in fibrin deposition, vascular thrombosis and tissue inflammation within an affected tissue, largely contributing to the innate arm of immunity. Through mFGL2’s actions of promoting vascular thrombosis and tissue inflammation, it has been implicated in the pathogenesis of viral-induced fulminant hepatitis in acute hepatitis B infections. Hepatocellular necrosis ensues rapidly, due to the HBV nucleocapsid protein’s ability to markedly upregulate expression of the mFGL2 prothrombinase, leading to fibrin deposition within the vasculature networks that supply blood to the liver. Secreted In addition to its constitutive secretion by CD4+ and CD8+ T cells, the secreted form of FGL2 (sFGL2) can be inducibly secreted by Foxp3+ CD4+ CD25+ T regulatory cells (Tregs). Such Treg cells play a vital role in dampening the immune response after the clearance of an infection to prevent sterile inflammation. These cells also play a fundamental role in maintaining self tolerance by suppressing the activation and expansion of self-reactive lymphocytes that may instigate autoimmunity.9 Through their roles in immune homeostasis, it has been shown that depletion of the Treg cell population in murine models for disease lead to enhanced immune responses to a variety of infectious agents including hepatitis C virus (HCV).10 Additionally, patients with a chronic HCV infection were shown to have higher counts of Treg cells in peripheral blood when compared with successfully treated or healthy controls.11 Secreted FGL2 (sFGL2) plays a role as a negative regulator of the Immune response. sFGL2 inhibits the adaptive immune response. Knockout mice for FGL2