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

Abstract

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.

• Authors: Di Wu, Hongwu Wang, Weiming Yan, Tao Chen, Ming Wang, Meifang Han, Zeguang Wu, Xiaojing Wang, Guo Ai, Dong Xi, Guanxin Shen, Xiaoping Luo, Qin Ning
• Journal: Immunologic research (Immunol Res) Vol. 64 Issue 2 Pg. 518-30 (Apr 2016) ISSN: 1559-0755 [Electronic] United States
• PMID: 26482053 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Fgl2 protein, mouse
• RNA, Small Interfering
• Fibrinogen

Topics

• Adoptive Transfer
• Animals
• Cytokines (metabolism)
• Disease Models, Animal
• Female
• Fibrinogen (genetics, metabolism)
• Gene Silencing
• Hepatitis, Viral, Animal (immunology, metabolism, mortality, therapy)
• Immunophenotyping
• Liver (immunology, metabolism, pathology)
• Lymphocyte Activation
• Mice
• Murine hepatitis virus (immunology)
• Phenotype
• RNA, Small Interfering (genetics)
• T-Lymphocyte Subsets (immunology, metabolism)