A disparate subset of double-negative T cells contributes to the outcome of murine fulminant viral hepatitis via effector molecule fibrinogen-like protein 2.
The underlying immune-mediated mechanisms involved in virus-induced severe hepatitis have not been well elucidated. In this study, we investigated the role of CD3(+)CD4(-)CD8(-) double-negative T (DN T) cells in the pathogenesis of fulminant viral hepatitis (FVH) induced by murine hepatitis virus strain 3 (MHV-3). After MHV-3 infection, the proportions of DN T cells increased significantly in BALB/cJ mice, and splenic DN T cells expressing high levels of CD69 were recruited by MHV-3-infected hepatocytes to the liver. Serum levels of alanine aminotransferase, aspartate aminotransferase and total bilirubin increased, accompanied by massive hepatocyte necrosis. These DN T cells were predominantly consisted of a TCRαβ(+) subset expressing high levels of CD44 and did not produce cytokine except IL-2. Adoptive transfer of this subset of DN T cells to the MHV-3-infected mice resulted in an increase in murine fibrinogen-like protein 2 (mfgl2) expressions in association with massive fibrin deposition in the liver. Following MHV-3 infection, membrane mfgl2 expression and functional procoagulant activity increased remarkably in the DN T cells. Introduction of a recombinant adenovirus which encoded a microRNA specifically targeting mfgl2 gene (Ad-mfgl2-miRNA) in vivo significantly inhibited the hepatic expression of mfgl2 and improved survival in mice. However, under this condition, adoptive transfer of the DN T cells accelerated the disease progression and reversed the benefit from mfgl2 gene silence, leading to a 100 % death rate. Our results demonstrate that DN T cells contribute to the outcome of MHV-3-induced FVH via an important effector molecule mfgl2.
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Di
D
Wu
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hongwu
H
Wang
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Weiming
W
Yan
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Tao
T
Chen
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Ming
M
Wang
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Meifang
M
Han
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Zeguang
Z
Wu
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Xiaojing
X
Wang
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Guo
G
Ai
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Dong
D
Xi
Institute of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Guanxin
G
Shen
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Xiaoping
X
Luo
Department of Infectious Disease, Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. qning@vip.sina.com.
Qin
Q
Ning
D019264:Adoptive Transfer; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006524:Hepatitis, Viral, Animal / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D016130:Immunophenotyping; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D006517:Murine hepatitis virus / Q000276:immunology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*
D016207:Cytokines; C490637:Fgl2 protein, mouse; D034741:RNA, Small Interfering; D005340:Fibrinogen
CD4−CD8− double-negative T cells; Fulminant viral hepatitis; Murine fibrinogen-like protein 2; Murine hepatitis virus strain 3