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Bennion KB, Liu D, Dawood AS, Wyatt MM, Alexander KL, Abdel-Hakeem MS, Paulos CM, Ford ML. CD8 + T cell-derived Fgl2 regulates immunity in a cell-autonomous manner via ligation of FcγRIIB. Nat Commun 2024; 15:5280. [PMID: 38902261 PMCID: PMC11190225 DOI: 10.1038/s41467-024-49475-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 06/07/2024] [Indexed: 06/22/2024] Open
Abstract
The regulatory circuits dictating CD8+ T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that tumor-infiltrating antigen-specific PD-1+ TCF-1- CD8+ T cells express the immunosuppressive cytokine Fgl2. Conditional deletion of Fgl2 specifically in mouse antigen-specific CD8+ T cells prolongs CD8+ T cell persistence, suppresses phenotypic and transcriptomic signatures of T cell exhaustion, and improves control of the tumor. In a mouse model of chronic viral infection, PD-1+ CD8+ T cell-derived Fgl2 also negatively regulates virus-specific T cell responses. In humans, CD8+ T cell-derived Fgl2 is associated with poorer survival in patients with melanoma. Mechanistically, the dampened responsiveness of WT Fgl2-expressing CD8+ T cells, when compared to Fgl2-deficient CD8+ T cells, is underpinned by the cell-intrinsic interaction of Fgl2 with CD8+ T cell-expressed FcγRIIB and concomitant caspase 3/7-mediated apoptosis. Our results thus illuminate a cell-autonomous regulatory axis by which PD-1+ CD8+ T cells both express the receptor and secrete its ligand in order to mediate suppression of anti-tumor and anti-viral immunity.
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Affiliation(s)
- Kelsey B Bennion
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
- Emory Winship Cancer Institute, Atlanta, GA, USA
- Cancer Biology PhD Program, Emory University, Atlanta, GA, USA
| | - Danya Liu
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
| | - Abdelhameed S Dawood
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA
- Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Megan M Wyatt
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
- Emory Winship Cancer Institute, Atlanta, GA, USA
- Cancer Biology PhD Program, Emory University, Atlanta, GA, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - Katie L Alexander
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
- Immunology and Molecular Pathogenesis PhD Program, Emory University, Atlanta, GA, USA
| | - Mohamed S Abdel-Hakeem
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA
- Pathology Advanced Translational Research Unit (PATRU), Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Chrystal M Paulos
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA
- Emory Winship Cancer Institute, Atlanta, GA, USA
- Cancer Biology PhD Program, Emory University, Atlanta, GA, USA
- Department of Microbiology and Immunology, Emory University, Atlanta, GA, USA
| | - Mandy L Ford
- Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
- Emory Winship Cancer Institute, Atlanta, GA, USA.
- Cancer Biology PhD Program, Emory University, Atlanta, GA, USA.
- Immunology and Molecular Pathogenesis PhD Program, Emory University, Atlanta, GA, USA.
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Fu L, Liu Z, Liu Y. Fibrinogen-like protein 2 in inflammatory diseases: A future therapeutic target. Int Immunopharmacol 2023; 116:109799. [PMID: 36764282 DOI: 10.1016/j.intimp.2023.109799] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 12/09/2022] [Accepted: 01/25/2023] [Indexed: 02/10/2023]
Abstract
Fibrinogen-like protein 2 (FGL2), a member of the fibrinogen family, exists as a membrane-bound protein with immune-associated coagulation activity and a soluble form possessing immunosuppressive functions. The immunomodulatory role of FGL2 is evident in fibrin deposition-associated inflammatory diseases and cancer, suggesting that FGL2 expression could be exploited as a disease biomarker and a therapeutic target. Recently, in vitro studies and knockout and transgenic animal FGL2 models have been used by us and others to reveal the involvement of FGL2 in the pathogenesis of various inflammatory diseases. This review summarizes our current knowledge of the immunomodulatory role of FGL2 in inflammatory diseases and examines the role of FGL2 as a potential therapeutic target.
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Affiliation(s)
- Li Fu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China
| | - Zheng Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China.
| | - Yang Liu
- Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Allergy and Clinical Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Clinical Research Center for Nasal Inflammatory Diseases, Wuhan, China.
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3
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Janssen E, Alosaimi MF, Alazami AM, Alsuliman A, Alaiya A, Al-Saud B, Al-Mousa H, Al-Zaid TJ, Smith E, Platt CD, Alruwaili H, Albanyan S, Al-Mayouf SM, Geha RS. A homozygous truncating mutation of FGL2 is associated with immune dysregulation. J Allergy Clin Immunol 2023; 151:572-578.e1. [PMID: 36243222 DOI: 10.1016/j.jaci.2022.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/15/2022] [Accepted: 10/07/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2-/- mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function. OBJECTIVE Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies. METHODS Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro. RESULTS The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2V205fs mutant failed to suppress T-cell proliferation. CONCLUSIONS We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient.
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Affiliation(s)
- Erin Janssen
- Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
| | - Mohammad F Alosaimi
- Immunology Research Laboratory, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Anas M Alazami
- Translational Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Abdullah Alsuliman
- Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ayodele Alaiya
- Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Bandar Al-Saud
- Department of Allergy and Immunology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hamoud Al-Mousa
- Department of Allergy and Immunology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Tariq Jassim Al-Zaid
- Department of Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Emma Smith
- Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Mass
| | - Craig D Platt
- Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Mass
| | - Hibah Alruwaili
- Translational Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Sarah Albanyan
- Department of Allergy and Immunology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Sulaiman M Al-Mayouf
- Department of Pediatric Rheumatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
| | - Raif S Geha
- Division of Immunology, Boston Children's Hospital and Harvard Medical School, Boston, Mass.
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4
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Sungnak W, Wagner A, Kowalczyk MS, Bod L, Kye YC, Sage PT, Sharpe AH, Sobel RA, Quintana FJ, Rozenblatt-Rosen O, Regev A, Wang C, Yosef N, Kuchroo VK. T Follicular Regulatory Cell-Derived Fibrinogen-like Protein 2 Regulates Production of Autoantibodies and Induction of Systemic Autoimmunity. THE JOURNAL OF IMMUNOLOGY 2020; 205:3247-3262. [PMID: 33168576 DOI: 10.4049/jimmunol.2000748] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 10/15/2020] [Indexed: 11/19/2022]
Abstract
T follicular regulatory (TFR) cells limit Ab responses, but the underlying mechanisms remain largely unknown. In this study, we identify Fgl2 as a soluble TFR cell effector molecule through single-cell gene expression profiling. Highly expressed by TFR cells, Fgl2 directly binds to B cells, especially light-zone germinal center B cells, as well as to T follicular helper (TFH) cells, and directly regulates B cells and TFH in a context-dependent and type 2 Ab isotype-specific manner. In TFH cells, Fgl2 induces the expression of Prdm1 and a panel of checkpoint molecules, including PD1, TIM3, LAG3, and TIGIT, resulting in TFH cell dysfunction. Mice deficient in Fgl2 had dysregulated Ab responses at steady-state and upon immunization. In addition, loss of Fgl2 results in expansion of autoreactive B cells upon immunization. Consistent with this observation, aged Fgl2-/- mice spontaneously developed autoimmunity associated with elevated autoantibodies. Thus, Fgl2 is a TFR cell effector molecule that regulates humoral immunity and limits systemic autoimmunity.
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Affiliation(s)
- Waradon Sungnak
- Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Allon Wagner
- Department of Electrical Engineering and Computer Science, Center for Computational Biology, University of California, Berkeley, CA 94720
| | - Monika S Kowalczyk
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Lloyd Bod
- Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Yoon-Chul Kye
- Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Peter T Sage
- Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.,Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
| | - Arlene H Sharpe
- Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.,Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115
| | - Raymond A Sobel
- Department of Pathology, Stanford University, Stanford, CA 94305; and
| | - Francisco J Quintana
- Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115
| | | | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142
| | - Chao Wang
- Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
| | - Nir Yosef
- Department of Electrical Engineering and Computer Science, Center for Computational Biology, University of California, Berkeley, CA 94720
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; .,Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142.,Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115
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Liu K, Li T, Huang S, Long R, You Y, Liu J, Wang Z. The reduced soluble fibrinogen-like protein 2 and regulatory T cells in acute coronary syndrome. Exp Biol Med (Maywood) 2015; 241:421-5. [PMID: 26515143 DOI: 10.1177/1535370215612138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 09/23/2015] [Indexed: 12/11/2022] Open
Abstract
Soluble fibrinogen-like protein 2, sfgl2, is the new effector of CD4(+)CD25(+)FOXP3(+) regulatory T cell (Treg) and exerts immunosuppressive activity. We design this study to investigate the possible role of sfgl2 in atherosclerosis. A total of 58 acute coronary syndrome (ACS) patients, together with 22 stable angina (SA) patients and 31 normal coronary artery (NCA) people were enrolled in our study. Serum level of sfgl2 and plasma level of Treg were respectively measured. In line with the change of Treg, serum level of sfgl2 in ACS (8.70 ng/mL) was significantly decreased (P = 0.003), compared with that in SA (11.86 ng/mL) and NCA (17.55 ng/mL). Both sfgl2 and Treg level were obviously decreased in ACS; Sfgl2 may play a protective role in atherosclerosis.
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Affiliation(s)
- Kun Liu
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 0086, China
| | - Ting Li
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 0086, China
| | - Shiyuan Huang
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 0086, China
| | - Rui Long
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 0086, China
| | - Ya You
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 0086, China
| | - Jinping Liu
- Department of Cardiac Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 0086, China
| | - Zhaohui Wang
- Department of Geriatrics, Institute of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 0086, China
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6
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Yang G, Hooper WC. Physiological functions and clinical implications of fibrinogen-like 2: A review. World J Clin Infect Dis 2013; 3:37-46. [PMID: 26161303 PMCID: PMC4495006 DOI: 10.5495/wjcid.v3.i3.37] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 07/23/2013] [Accepted: 08/17/2013] [Indexed: 02/06/2023] Open
Abstract
Fibrinogen-like 2 (FGL2) encompasses a transmembrane (mFGL2) and a soluble (sFGL2) form with differential tertiary structure and biological activities. Typically, mFGL2 functions as prothrombinase that is capable of initiating coagulation in tissue without activation of the blood clotting cascade, whereas sFGL2 largely acts as an immunosuppressor that can repress proliferation of alloreactive T lymphocytes and maturation of bone marrow dendritic cells. Protein sequences of FGL2 exhibit evolutionary conservation across wide variety of species, especially at the carboxyl terminus that contains fibrinogen related domain (FRED). The FRED of FGL2 confers specificity and complexity in the action of FGL2, including receptor recognition, calcium affiliation, and substrate binding. Constitutive expression of FGL2 during embryogenesis and in mature tissues suggests FGL2 might be physiologically important. However, excessive induction of FGL2 under certain medical conditions (e.g., pathogen invasion) could trigger complement activation, inflammatory response, cellular apoptosis, and immune dysfunctions. On the other hand, complete absence of FGL2 is also detrimental as lack of FGL2 can cause autoimmune glomerulonephritis and acute cellular rejection of xenografts. All these roles involve mFGL2, sFGL2, or their combination. Although it is not clear how mFGL2 is cleaved off its host cells and secreted into the blood, circulating sFGL2 has been found correlated with disease severity and viral loading among patients with human hepatitis B virus or hepatitis C virus infection. Further studies are warranted to understand how FGL2 expression is regulated under physiological and pathological conditions. Even more interesting is to determine whether mFGL2 can fulfill an immunoregulatory role through its FRED at carboxyl end of the molecule and, and vice versa, whether sFGL2 is procoagulant upon binding to a target cell. Knowledge in this area should shed light on development of sFGL2 as an alternative immunosuppressive agent for organ transplantation or as a biomarker for predicting disease progression, monitoring therapeutic effects, and targeting FGL2 for repression in ameliorating fulminant viral hepatitis.
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Fibrinogen-like protein 2 expression correlates with microthrombosis in rats with type 2 diabetic nephropathy. J Biomed Res 2013; 25:120-7. [PMID: 23554679 PMCID: PMC3596703 DOI: 10.1016/s1674-8301(11)60015-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2010] [Revised: 11/07/2010] [Accepted: 01/11/2011] [Indexed: 12/21/2022] Open
Abstract
Fibrinogen-like protein 2 (fgl2), a novel prothrombinase, is involved in microthrombosis. We examined fgl2 expression in the glomerular and tubulointerstitial capillaries and its correlation with microthromsis in rats with streptozocin-induced type 2 diabetic nephropathy. Our RT-PCR and immunoblotting analysis showed that fgl2 mRNA and protein levels were increased in microvascular endothelial cells of the glomeruli and renal interstitia at week 19 and became significantly elevated with the development of diabetic nephropathy (P < 0.01). Fgl2 was not or only weakly expressed in the renal tissues of normal rats. Furthermore, a direct significant correlation (r = 0.543, P < 0.01) was found between fgl2 expression and microthrombotic capillaries in the renal tissues. Enzyme linked immunosorbent assays (ELISA) additionally showed that circulating TNF-α levels in rats with type 2 diabetes were significantly elevated and closely correlated with fgl2 expression (r = 0.871, P < 0.01). Our results suggest that fgl2 may activate renal microthrombosis, thus contributing to glomerular hypertension and renal ischemia.
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Shalev I, Wong KM, Foerster K, Zhu Y, Chan C, Maknojia A, Zhang J, Ma XZ, Yang XC, Gao JF, Liu H, Selzner N, Clark DA, Adeyi O, Phillips MJ, Gorczynski RR, Grant D, McGilvray I, Levy G. The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis. Hepatology 2009; 49:387-97. [PMID: 19085958 DOI: 10.1002/hep.22684] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
UNLABELLED Fulminant viral hepatitis (FH) remains an important clinical problem in which the underlying pathogenesis is not well understood. Here, we present insight into the immunological mechanisms involved in FH caused by murine hepatitis virus strain 3 (MHV-3), indicating a critical role for CD4(+)CD25(+) regulatory T cells (Tregs) and production of the novel Treg effector molecule FGL2. Before infection with MHV-3, susceptible BALB/cJ mice had increased numbers of Tregs and expression of fgl2 messenger RNA (mRNA) and FGL2 protein compared with resistant A/J mice. After MHV-3 infection, plasma levels of FGL2 in BALB/cJ mice were significantly increased, correlating with increased percentage of Tregs. Treatment with anti-FGL2 antibody completely inhibited Treg activity and protected susceptible BALB/cJ mice against MHV-3-liver injury and mortality. Adoptive transfer of wild-type Tregs into resistant fgl2(-/-) mice increased their mortality caused by MHV-3 infection, whereas transfer of peritoneal exudate macrophages had no adverse effect. CONCLUSION This study demonstrates that FGL2 is an important effector cytokine of Tregs that contributes to susceptibility to MHV-3-induced FH. The results further suggest that targeting FGL2 may lead to the development of novel treatment approaches for acute viral hepatitis infection.
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Affiliation(s)
- Itay Shalev
- Multi Organ Transplant Program, University of Toronto, Toronto, Ontario, Canada
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9
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Shalev I, Liu H, Koscik C, Bartczak A, Javadi M, Wong KM, Maknojia A, He W, Liu MF, Diao J, Winter E, Manuel J, McCarthy D, Cattral M, Gommerman J, Clark DA, Phillips MJ, Gorczynski RR, Zhang L, Downey G, Grant D, Cybulsky MI, Levy G. Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis. THE JOURNAL OF IMMUNOLOGY 2008; 180:249-60. [PMID: 18097026 DOI: 10.4049/jimmunol.180.1.249] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Mice with targeted deletion of fibrinogen-like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild-type recipients reconstituted with fgl2-/- bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, Th 1 polarization, and increased numbers of Ab-producing B cells following immunization with T-independent Ags. Dendritic cells were more abundant in fgl2-/- mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2-/- mice, but their suppressive activity was significantly impaired. Ab to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited dendritic cell maturation and induced apoptosis of B cells through binding to the low-affinity FcgammaRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease.
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Affiliation(s)
- Itay Shalev
- Multi Organ Transplant Program, Department of Immunology, University of Toronto, Ontario, Canada
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