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Journal of Virology, October 2008, p. 9564-9576, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00927-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

T Cells Initiate Acute Inflammation and Injury in Adenovirus-Infected Liver via Cytokine-Chemokine Cross Talk

Maureen N. Ajuebor,^1* Yijun Jin,¹ Griffin L. Gremillion,¹ Robert M. Strieter,² Qingling Chen,¹ and Patrick A. Adegboyega³

Department of Molecular and Cellular Physiology,¹ Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, Louisiana,³ Department of Medicine, University of Virginia, Charlottesville, Virginia²

Received 5 May 2008/ Accepted 17 July 2008

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 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 T cells in the livers of mice infected with Ad expressing the Escherichia coli LacZ gene (AdLacZ). We also showed a critical role for T cells in initiating acute liver toxicity after AdLacZ administration, driven in part by the ability of 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 T-cell-deficient mice was associated with lower hepatic levels of gamma interferon (IFN-) and CXCL9, an IFN--inducible chemokine. Finally, our study highlighted a key role for IFN- and CXCL9 cross talk acting in a feedback loop to drive the proinflammatory effects of T cells during AdLacZ-mediated acute liver toxicity. Specifically, intracellular IFN- produced by activated hepatic T cells interacts with hepatocytes to mediate hepatic CXCL9 production, with the consequent accumulation of CXCR3-bearing T cells in the liver to cause acute liver damage without vector clearance.

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* Corresponding author. Mailing address: Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. Phone: (318) 675-4199. Fax: (318) 675-4156. E-mail: majueb{at}lsuhsc.edu

Published ahead of print on 30 July 2008.

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Journal of Virology, October 2008, p. 9564-9576, Vol. 82, No. 19
0022-538X/08/$08.00+0     doi:10.1128/JVI.00927-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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