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

Olga Luft, Ramzi Khattar, Kaveh Farrokhi, Dario Ferri, Nataliya Yavorska, Jianhua Zhang, Hassan Sadozai, Oyedele Adeyi, Andrzej Chruscinski, Gary A. Levy, Nazia Selzner

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)476-489
Number of pages14
JournalImmunology
Volume154
Issue number3
DOIs
StatePublished - Jul 2018

Bibliographical note

Funding Information:
We would like to thank Dr M. Oldstone for LCMV cl-13 and Dr P. Ohashi for the antibody to LCMV (VL4). Dr Nazia Selzner and Dr Gary Levy are recipients of grants from the Canadian Institute of Health Research (Grant 136781) and the Physician Services Incorporated (Grant 12-06).

Publisher Copyright:
© 2018 John Wiley & Sons Ltd

Keywords

  • chronic infection
  • fibrinogen-like protein 2
  • T-cell exhaustion

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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