The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis.
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.
Shalev
Itay
I
Multi Organ Transplant Program, University of Toronto, Toronto, Ontario, Canada.
Wong
Kit Man
KM
Foerster
Katharina
K
Zhu
Yi
Y
Chan
Cecilia
C
Maknojia
Asif
A
Zhang
Jianhua
J
Ma
Xue-Zhong
XZ
Yang
Xiao Chun
XC
Gao
Julia Fang
JF
Liu
Hao
H
Selzner
Nazia
N
Clark
David A
DA
Adeyi
Oyedele
O
Phillips
M James
MJ
Gorczynski
Reginald R
RR
Grant
David
D
McGilvray
Ian
I
Levy
Gary
G
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*
C490637:Fgl2 protein, mouse; D005340:Fibrinogen