GammadeltaT 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 gammadeltaT 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 gammadeltaT cells in the livers of mice infected with Ad expressing the Escherichia coli LacZ gene (AdLacZ). We also showed a critical role for gammadeltaT cells in initiating acute liver toxicity after AdLacZ administration, driven in part by the ability of gammadeltaT cells to promote the recruitment of the conventional T cell, the CD8(+) T cell, into the liver. Furthermore, reduced hepatic injury in AdLacZ-infected gammadeltaT-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 gammadeltaT cells during AdLacZ-mediated acute liver toxicity. Specifically, intracellular IFN-gamma produced by activated hepatic gammadeltaT cells interacts with hepatocytes to mediate hepatic CXCL9 production, with the consequent accumulation of CXCR3-bearing gammadeltaT cells in the liver to cause acute liver damage without vector clearance.
Ajuebor
Maureen N
MN
Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA.
Jin
Yijun
Y
Gremillion
Griffin L
GL
Strieter
Robert M
RM
Chen
Qingling
Q
Adegboyega
Patrick A
PA
D000256:Adenoviridae / Q000378:metabolism; D000257:Adenoviridae Infections / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000821:virology*; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D007249:Inflammation; D007371:Interferon-gamma / Q000235:genetics; D008099:Liver / Q000276:immunology* / Q000821:virology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D018925:Chemokines; D016207:Cytokines; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma