Liver TCRγδ(+) CD3(+) CD4(-) CD8(-) T cells contribute to murine hepatitis virus strain 3-induced hepatic injury through a TNF-α-dependent pathway

Abstract

The mechanisms of each subset of immune cells contributing to the pathogenesis of viral hepatitis remain incompletely understood. In this study, we examined the role of liver CD4(-) CD8(-) (double negative, DN) T cells during murine hepatitis virus strain 3 (MHV-3)-induced hepatitis in C3H/HeJ mice. We demonstrate that predominant population of DN T cells in the liver of healthy or MHV-3-infected mice express TCRγδ(+). The proportion of TCRγδ(+) DN T cells in liver CD3(+) T cells was markedly increased after MHV-3 infection. Adoptive transfer of TCRγδ(+) DN T cells led to dramatically decreased survival in MHV-3-infected mice, accompanied by deteriorated histopathology and elevated ALT and AST levels. It was found that these cells were hyperactivated after MHV-3 infection with a production of TNF-α, IFN-γ, IL-2 and IL-17A. Highly activated liver TCRγδ(+) DN T cells were cytotoxic to MHV-3-infected hepatocytes in vitro and this effect did not require cell-cell contact. Moreover, the cytotoxic effect of liver TCRγδ(+) DN T cells against hepatocytes involves TNF-α pathway, but not IL-17A or IFN-γ. These results indicate that liver TCRγδ(+) DN T cells play a critical role in the liver injury in MHV-3-induced hepatitis, via a TNF-α dependent pathway.