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

Immunology. 2018 Jul;154(3):476-489. doi: 10.1111/imm.12897. Epub 2018 Feb 20.

Abstract

Persistent viruses evade immune detection by interfering with virus-specific innate and adaptive antiviral immune responses. Fibrinogen-like protein-2 (FGL2) is a potent effector molecule of CD4+ CD25+ FoxP3+ regulatory T cells and exerts its immunosuppressive activity following ligation to its cognate receptor, FcγRIIB/RIII. The role of FGL2 in the pathogenesis of chronic viral infection caused by lymphocytic choriomeningitis virus clone-13 (LCMV cl-13) was assessed in this study. Chronically infected fgl2+/+ mice had increased plasma levels of FGL2, with reduced expression of the maturation markers, CD80, CD86 and MHC-II on macrophages and dendritic cells and impaired production of neutralizing antibody. In contrast, fgl2-/- mice or fgl2+/+ mice that had been pre-treated with antibodies to FGL2 and FcγRIIB/RIII and then infected with LCMV cl-13 developed a robust CD4+ and CD8+ antiviral T-cell response, produced high titred neutralizing antibody to LCMV and cleared LCMV. Treatment of mice with established chronic infection with antibodies to FGL2 and FcγRIIB/RIII was shown to rescue the number and functionality of virus-specific CD4+ and CD8+ T cells with reduced total and virus-specific T-cell expression of programmed cell death protein 1 leading to viral clearance. These results demonstrate an important role for FGL2 in viral immune evasion and provide a rationale to target FGL2 to treat patients with chronic viral infection.

Keywords: T-cell exhaustion; chronic infection; fibrinogen-like protein 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibodies, Viral / immunology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism*
  • Biomarkers
  • Female
  • Fibrinogen / genetics
  • Fibrinogen / metabolism*
  • Gene Expression
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Immunophenotyping
  • Lymphocytic Choriomeningitis / genetics
  • Lymphocytic Choriomeningitis / immunology*
  • Lymphocytic Choriomeningitis / metabolism*
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Mice, Knockout
  • Receptors, IgG / metabolism*
  • Signal Transduction
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Viral Load

Substances

  • Antibodies, Neutralizing
  • Antibodies, Viral
  • Biomarkers
  • Fcgr2b protein, mouse
  • Fcgr3 protein, mouse
  • Fgl2 protein, mouse
  • Receptors, IgG
  • Fibrinogen

Grant support