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

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.