17 CD4+CD25+Foxp3+ Treg can also modulate the activity of DC though the expression of various cell surface molecules. Treg are known to express high levels of cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which can downregulate the expression of the important co-stimulatory molecules CD80 and CD86 on DC. CTLA-4 is thought to bind directly to and capture these co-stimulatory molecules in aRambam Maimonides Medical JournalJuly 2015 Volume 6 Issue 3 eTreg and FGL2 in Alloimmunity and AutoimmunityFigure 1. Mechanisms of Treg-mediated Immune Suppression. Treg suppress immune responses through molecular pathways that act directly on T cells or indirectly through antigen-presenting cells such as dendritic cells. These molecular mechanisms are described in Table 1. FGL2 binds to FcRIIB on dendritic cells to inhibit dendritic cell maturation. DC, dendritic cell; IL-2R, IL-2 receptor; Teff, effector T cell; Treg, regulatory T cell.process known as trans-endocytosis.18 The LAG-3 molecule is a surface molecule of Treg that is thought to inhibit DC by binding to major histocompatibility complex (MHC) class II. This binding transmits an inhibitory signal that prevents DC maturation and reduces co-stimulatory activity.19 More recently, the surface molecule T cell immunoreceptor with Ig and ITIM domains (TIGIT) has been identified as a marker of a highly suppressive population of CD4+CD25+Foxp3+ Treg. The receptor for TIGIT is the poliovirus receptor (PVR) on DC.20 A recent report by Joller et al. demonstrated that TIGIT+ Treg express large amounts of the Treg effector molecule FGL2. Furthermore, the suppression of Th1 and Th17 but not Th2 responses by TIGIT+ Treg was dependent on FGL2.21 In vivo, FGL2 was critical in the control of effector T cell expansion by TIGIT+ Treg in lymphopenic hosts and in controlling a number of inflammatory diseases including colitis.21 FIBRINOGEN-LIKE PROTEIN 2 IS A TREG EFFECTOR MOLECULE Fibrinogen-like protein 2 (FGL2), or RRx-001 supplier fibroleukin, was originally cloned from a cDNA library made from cytotoxic T cells. The fgl2 gene is localized to the proximal region of chromosome 5 in mice, 7q11.23 in humans, and 9 in pigs.22,23 The longest open reading frame encodes a 432-, 439-, and 442amino acid protein in mice, humans, and pigs,Rambam Maimonides Medical Journalrespectively.23 The FGL2 protein is highly homologous between species (78 homology between mouse and human and 89 homology between pig and human), with greater conservation at the carboxyl terminus. The fully glycosylated FGL2 protein shows molecular sizes of approximately 65?0 kiloDaltons (kDa) and 260?80 kDa under reducing and non-reducing SCIO-469 web conditions, respectively, suggesting that it has a tetrameric structure.24?6 Amino acid sequence analysis of FGL2 reveals an Nterminal hydrophobic motif, predicted as either the transmembrane domain or a signal peptide, with a carboxyl-terminal domain highly homologous (36 ) to the fibrinogen beta and gamma subunits, the socalled fibrinogen-related domain (FRED).23,25,27 Thus FGL2 is classified as a member of the fibrinogen-related family of proteins, which also includes tenascin, angiopoietin, and ficolin.28 Fibrinogen-like protein 2 has been shown to exist both as a membrane-bound protein and as a secreted molecule. The biological function of FGL2 was first documented in a murine fulminant hepatitis model, in which FGL2 expression is induced in macrophages and endothelial cells, leading to a novel tissue factor-independ.17 CD4+CD25+Foxp3+ Treg can also modulate the activity of DC though the expression of various cell surface molecules. Treg are known to express high levels of cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which can downregulate the expression of the important co-stimulatory molecules CD80 and CD86 on DC. CTLA-4 is thought to bind directly to and capture these co-stimulatory molecules in aRambam Maimonides Medical JournalJuly 2015 Volume 6 Issue 3 eTreg and FGL2 in Alloimmunity and AutoimmunityFigure 1. Mechanisms of Treg-mediated Immune Suppression. Treg suppress immune responses through molecular pathways that act directly on T cells or indirectly through antigen-presenting cells such as dendritic cells. These molecular mechanisms are described in Table 1. FGL2 binds to FcRIIB on dendritic cells to inhibit dendritic cell maturation. DC, dendritic cell; IL-2R, IL-2 receptor; Teff, effector T cell; Treg, regulatory T cell.process known as trans-endocytosis.18 The LAG-3 molecule is a surface molecule of Treg that is thought to inhibit DC by binding to major histocompatibility complex (MHC) class II. This binding transmits an inhibitory signal that prevents DC maturation and reduces co-stimulatory activity.19 More recently, the surface molecule T cell immunoreceptor with Ig and ITIM domains (TIGIT) has been identified as a marker of a highly suppressive population of CD4+CD25+Foxp3+ Treg. The receptor for TIGIT is the poliovirus receptor (PVR) on DC.20 A recent report by Joller et al. demonstrated that TIGIT+ Treg express large amounts of the Treg effector molecule FGL2. Furthermore, the suppression of Th1 and Th17 but not Th2 responses by TIGIT+ Treg was dependent on FGL2.21 In vivo, FGL2 was critical in the control of effector T cell expansion by TIGIT+ Treg in lymphopenic hosts and in controlling a number of inflammatory diseases including colitis.21 FIBRINOGEN-LIKE PROTEIN 2 IS A TREG EFFECTOR MOLECULE Fibrinogen-like protein 2 (FGL2), or fibroleukin, was originally cloned from a cDNA library made from cytotoxic T cells. The fgl2 gene is localized to the proximal region of chromosome 5 in mice, 7q11.23 in humans, and 9 in pigs.22,23 The longest open reading frame encodes a 432-, 439-, and 442amino acid protein in mice, humans, and pigs,Rambam Maimonides Medical Journalrespectively.23 The FGL2 protein is highly homologous between species (78 homology between mouse and human and 89 homology between pig and human), with greater conservation at the carboxyl terminus. The fully glycosylated FGL2 protein shows molecular sizes of approximately 65?0 kiloDaltons (kDa) and 260?80 kDa under reducing and non-reducing conditions, respectively, suggesting that it has a tetrameric structure.24?6 Amino acid sequence analysis of FGL2 reveals an Nterminal hydrophobic motif, predicted as either the transmembrane domain or a signal peptide, with a carboxyl-terminal domain highly homologous (36 ) to the fibrinogen beta and gamma subunits, the socalled fibrinogen-related domain (FRED).23,25,27 Thus FGL2 is classified as a member of the fibrinogen-related family of proteins, which also includes tenascin, angiopoietin, and ficolin.28 Fibrinogen-like protein 2 has been shown to exist both as a membrane-bound protein and as a secreted molecule. The biological function of FGL2 was first documented in a murine fulminant hepatitis model, in which FGL2 expression is induced in macrophages and endothelial cells, leading to a novel tissue factor-independ.