title: The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Multi Organ Transplant Program, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Itay
authors.initials: I
authors.lastname: Shalev
authors.forename: Kit Man
authors.initials: KM
authors.lastname: Wong
authors.forename: Katharina
authors.initials: K
authors.lastname: Foerster
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Cecilia
authors.initials: C
authors.lastname: Chan
authors.forename: Asif
authors.initials: A
authors.lastname: Maknojia
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Ma
authors.forename: Xiao Chun
authors.initials: XC
authors.lastname: Yang
authors.forename: Julia Fang
authors.initials: JF
authors.lastname: Gao
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Nazia
authors.initials: N
authors.lastname: Selzner
authors.forename: David A
authors.initials: DA
authors.lastname: Clark
authors.forename: Oyedele
authors.initials: O
authors.lastname: Adeyi
authors.forename: M James
authors.initials: MJ
authors.lastname: Phillips
authors.forename: Reginald R
authors.initials: RR
authors.lastname: Gorczynski
authors.forename: David
authors.initials: D
authors.lastname: Grant
authors.forename: Ian
authors.initials: I
authors.lastname: McGilvray
authors.forename: Gary
authors.initials: G
authors.lastname: Levy
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018352:Coronavirus Infections / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005340:Fibrinogen / Q000276:immunology*; D005434:Flow Cytometry; D006524:Hepatitis, Viral, Animal / Q000276:immunology*; D007165:Immunosuppression Therapy; D051379:Mice; D008805:Mice, Inbred A / Q000276:immunology; D008807:Mice, Inbred BALB C; D006517:Murine hepatitis virus; D016133:Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C490637:Fgl2 protein, mouse; D005340:Fibrinogen