A disparate subset of double-negative T cells contributes to the outcome of murine fulminant viral hepatitis via effector molecule fibrinogen-like protein 2

• Published in: Immunologic research Vol. 64; no. 2; pp. 518 - 530
• Main Authors: Wu, Di, Wang, Hongwu, Yan, Weiming, Chen, Tao, Wang, Ming, Han, Meifang, Wu, Zeguang, Wang, Xiaojing, Ai, Guo, Xi, Dong, Shen, Guanxin, Luo, Xiaoping, Ning, Qin
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.04.2016; Springer Nature B.V
• Subjects: Adenoviridae; Adenovirus; Adoptive Transfer; Allergology; Animals; Biomedical and Life Sciences; Biomedicine; Coronaviridae; Cytokines - metabolism; Disease Models, Animal; Female; Fibrinogen - genetics; Fibrinogen - metabolism; Gene Silencing; Hepatitis; Hepatitis, Viral, Animal - immunology; Hepatitis, Viral, Animal - metabolism; Hepatitis, Viral, Animal - mortality; Hepatitis, Viral, Animal - therapy; Immune system; Immunology; Immunophenotyping; Internal Medicine; Liver - immunology; Liver - metabolism; Liver - pathology; Lymphocyte Activation; Lymphocytes; Medicine/Public Health; Mice; Murine hepatitis virus; Murine hepatitis virus - immunology; Original Article; Phenotype; Protein expression; RNA, Small Interfering - genetics; Rodents; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Fulminant viral hepatitis; CD4; Murine fibrinogen-like protein 2; Murine hepatitis virus strain 3; CD8; double-negative T cells; CD4−CD8− double-negative T cells
• ISSN: 0257-277X; 1559-0755
• DOI: 10.1007/s12026-015-8727-0

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.