Soluble Fibrinogen-Like Protein 2/Fibroleukin Exhibits Immunosuppressive Properties: Suppressing T Cell Proliferation and Inhibiting Maturation of Bone Marrow-Derived Dendritic Cells

Chan, Chun Man; Kay, Lyndsey S.; Khadaroo, Rachel G.; Chan, Man Khun; Lakatoo, Sophia; Young, Kelvin; Zhang, Li; Gorczynski, Reginald M.; Cattral, Mark S.; Rotstein, Ori D.; Levy, Gary

doi:10.4049/jimmunol.170.8.4036

Cited by 134 publications

(175 citation statements)

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“…Accordingly, some of the effects mediated by alteration of fgl2 expression might reflect not simply altered thrombin deposition, but also an altered immune activation. As but one example, Chan et al (23) reported that fgl2 modified expression of costimulatory molecules on developing dendritic cells, with a profound "downstream" effect on cytokine induction following allostimulation. Current studies from our laboratory support the hypothesis that an additional immunomodulatory role for fgl2 does indeed follow binding to a receptor expressed in multiple tissues (R. Liu, manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

Ning

Sun

Han

et al. 2005

The Journal of Immunology

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Immune coagulation is a major contributor to the pathogenesis of xenograft rejection, viral-induced hepatocellular injury and cytokine-induced fetal loss syndrome. In this study, we investigated the contribution of the novel gene product, fibrinogen-like protein 2 (fgl2) prothrombinase, in mediating immune injury in experimental and human acute allograft rejection. Using a mouse heterotopic cardiac transplant model, mouse fgl2(mfgl2)/fibroleukin mRNA transcripts and protein were highly expressed in macrophages, CD4- and CD8-positive T lymphocytes, and endothelial cells in rejecting cardiac allografts in association with deposits of fibrin. Although mfgl2-deficient mice rejected allografts at similar rates to littermate controls, survival of grafts from mfgl2-deficient mice were prolonged and deposition of intravascular fibrin was diminished. Treatment of wild-type mice with a neutralizing anti-fgl2 Ab ameliorated histological evidence for allorejection and intravascular fibrin deposition, and resulted in an increase in graft survival. To address further the relevance of fgl2 in acute allograft rejection, we examined kidney biopsies from patients who had undergone renal transplantation. Human fgl2 mRNA transcripts and protein were markedly expressed mainly in renal tubule cells, infiltrating lymphoid cells including macrophages, CD8+ T cells, mature B cells (plasma cells), and endothelial cells. Dual staining showed fibrin deposition was localized mainly to blood vessels, in the glomerulus and interstitium and the lumen of tubules, and occurred in association with human fgl2 expression. These data collectively suggest that fgl2 accounts for the fibrin deposition seen in both experimental and human allograft rejection and provide a rationale for targeting fgl2 as adjunctive therapy to treat allograft rejection.

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Section: Discussionmentioning

confidence: 99%

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

Ning

Sun

Han

et al. 2005

The Journal of Immunology

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“…26 Previously we reported that in addition to its role in innate immunity as a membraneassociated prothrombinase, FGL2 also may have an important role in adaptive immune responses, similar to other members of the fibrinogen-like family of proteins, which include tenascin and angiopoietin. 27 Recombinant FGL2 was shown previously to suppress T cell proliferation to alloantigens, anti-CD3/CD28 antibodies, and Con A. 27 FGL2 also has been shown to inhibit maturation of bone marrow-derived dendritic cells (DCs) and polarized an allogeneic immune response toward a Th2 cytokine profile.…”

Section: Discussionmentioning

confidence: 99%

“…27 Recombinant FGL2 was shown previously to suppress T cell proliferation to alloantigens, anti-CD3/CD28 antibodies, and Con A. 27 FGL2 also has been shown to inhibit maturation of bone marrow-derived dendritic cells (DCs) and polarized an allogeneic immune response toward a Th2 cytokine profile. 27 In fgl2-deficient mice, Th1 cytokine levels and activity of DC, B, and T cells were all increased.…”

Section: Discussionmentioning

confidence: 99%

“…27 FGL2 also has been shown to inhibit maturation of bone marrow-derived dendritic cells (DCs) and polarized an allogeneic immune response toward a Th2 cytokine profile. 27 In fgl2-deficient mice, Th1 cytokine levels and activity of DC, B, and T cells were all increased. 28 Levels of FGL2 in the plasma correlated with numbers of Tregs in both resistant and susceptible strains of mice before and after MHV-3 infection (Figs.…”

Section: Discussionmentioning

confidence: 99%

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The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis #

et al. 2009

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“…3c). This analysis suggested several such mechanisms, including suppressive soluble factors [12][13][14] , generation of extracellular adenosine [15][16][17][18] , and release of reactive oxygen 19 , and a possible, previously unanticipated role for T R cells in regulating wound repair.…”

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confidence: 99%

Foxp3-dependent programme of regulatory T-cell differentiation

Gavin

Rasmussen²,

Fontenot³

et al. 2007

Nature

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889

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Regulatory CD4 1 T cells (T R cells), the development of which is critically dependent on X-linked transcription factor Foxp3 (forkhead box P3), prevent self-destructive immune responses 1 . Despite its important role, molecular and functional features conferred by Foxp3 to T R precursor cells remain unknown. It has been suggested that Foxp3 expression is required for both survival of T R precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such 'anergy' and T R suppressive capacity are intimately linked 2-4 . Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of T R cells. Although its function is required for T R cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of T R cells, including anergy and dependence on paracrine IL-2. Furthermore, Foxp3 solidifies T R cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain T R cells. This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for T R cell homeostasis.In males, Foxp3 deficiency results in fatal early-onset systemic autoimmune disease 5 . In heterozygote Foxp3 wt/null females only one-half of T cells harbours the mutant Foxp3 allele due to random X-chromosome inactivation, whereas autoimmunity is controlled by a normal T R population expressing the Foxp3 wild-type allele. Thus, we were able to genetically mark cells actively transcribing a Foxp3 null allele, yet lacking Foxp3 protein (hereafter called T FN for Foxp3 nullexpressing T cells), through an in-frame insertion of GFP into a stop-codon-disrupted Foxp3 locus (Foxp3 gfpko ) and investigate their features in mice ( Fig. 1a; see also Supplementary Figs 1 and 2a). Female Foxp3 gfpko/wt mice were healthy, whereas male Foxp3 gfpko mice developed the same severity of autoimmunity as Foxp3 knockout (Foxp3 null ) mice 6 , resulting in death at ,4 weeks of age. Thymocyte and peripheral lymphoid organ cellularity did not differ between Foxp3 gfpko/wt and Foxp3 gfp/gfp mice, nor did the proportion of Foxp3 1 T R cells and Foxp3 2 CD4 1 T cells (data not shown). As our main focus was to characterize T FN cells in healthy Foxp3 gfpko/wt mice, analysis of autoimmune male Foxp3 gfpko mice is included as Supplementary Fig. 2.T FN cells constituted ,1-3% of mature CD4 1 thymocytes and peripheral CD4 1 T cells, indicating that Foxp3 is not required to rescue T R precursors from negative selection (Fig. 1b, c). This is consistent with a reported abundance of T-cell receptors (TCRs) characteristic of T R cells in Foxp3 null mice 7 . As ectopic expression of Foxp3 has been shown to induce a state of hyporesponsiveness in CD4 1 T cell...

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Soluble Fibrinogen-Like Protein 2/Fibroleukin Exhibits Immunosuppressive Properties: Suppressing T Cell Proliferation and Inhibiting Maturation of Bone Marrow-Derived Dendritic Cells

Cited by 134 publications

References 38 publications

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

Role of Fibrinogen-Like Protein 2 Prothrombinase/Fibroleukin in Experimental and Human Allograft Rejection

The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis #

Foxp3-dependent programme of regulatory T-cell differentiation

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