γδT cells initiate acute inflammation and injury in adenovirus-infected liver via cytokine-chemokine cross talk

Emerging studies suggest an important role for the innate immune response in replication-defective adenovirus (Ad)-mediated acute liver toxicity. Specifically, classical innate immune cells (including NK cells, neutrophils, and Kupffer cells) have all been implicated in the development of Ad-mediated acute liver toxicity. The nonclassical innate immune T cell, the gamma delta T cell, has been implicated in the pathophysiology of several viral infections that predominantly affect the mucosa and brain, but the specific role in the pathology of AdLacZ-mediated acute liver inflammation and injury as well as accompanying vector clearance is largely unknown. In the present study, we demonstrated that a CXCL9-CXCR3-dependent mechanism governed the accumulation of gamma delta T cells in the livers of mice infected with Ad expressing the Escherichia coli LacZ gene (AdLacZ). We also showed a critical role for gamma delta T cells in initiating acute liver toxicity after AdLacZ administration, driven in part by the ability of gamma delta T cells to promote the recruitment of the conventional T cell, the CD8(+) T cell, into the liver. Furthermore, reduced hepatic injury in AdLacZ-infected gamma delta T-cell-deficient mice was associated with lower hepatic levels of gamma interferon (IFN-gamma) and CXCL9, an IFN-gamma-inducible chemokine. Finally, our study highlighted a key role for IFN-gamma and CXCL9 cross talk acting in a feedback loop to drive the proinflammatory effects of gamma delta T cells during AdLacZ-mediated acute liver toxicity. Specifically, intracellular IFN-gamma produced by activated hepatic gamma delta T cells interacts with hepatocytes to mediate hepatic CXCL9 production, with the consequent accumulation of CXCR3-bearing gamma delta T cells in the liver to cause acute liver damage without vector clearance.