V(alpha)14iNKT cells promote liver pathology during adenovirus infection by inducing CCL5 production: implications for gene therapy.
Replication-defective recombinant adenoviruses are the most widely studied replication-defective vectors for the potential treatment of inherited human diseases. However, broad clinical application of replication-defective adenoviruses in gene therapy is being hindered by the induction of vigorous innate and adaptive immune responses against the vector that cause deleterious effects in the liver. V(alpha)14 invariant natural killer T cells (V(alpha)14iNKT cells) are thymus-derived innate T cells at the interface between the two arms of the immune response and provide full engagement of host defense. The pathophysiological role of intrahepatic V(alpha)14iNKT cells during replication-defective adenovirus infection is not known and is the main focus of our study. Our data showed that intrahepatic V(alpha)14iNKT cells were activated in response to adenovirus infection to induce significant levels of hepatic chemokine (C-C motif) ligand 5 (CCL5) and subsequent liver toxicity. Moreover, intrahepatic CCL5 production was selectively reduced by V(alpha)14iNKT cell deficiency. In vivo studies utilizing CCL5-deficient mice or V(alpha)14iNKT cell-deficient mice demonstrated that CCL5 deficiency or V(alpha)14iNKT cell deficiency was associated with reduced liver pathology. Similar results were seen after blocking the biological effects of the CCL5 receptors. In conclusion, we have identified an important proinflammatory role for activated intrahepatic V(alpha)14iNKT cells in positively influencing hepatic CCL5 production to promote acute liver inflammation and injury. Therefore, our findings highlight the blockade of CCL5 interaction with a cognate receptor(s) as an important potential strategy to alleviate liver pathology associated with replication-defective adenovirus infection.
Ajuebor
Maureen N
MN
Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana 71130, USA. majueb@lsuhsc.edu
Chen
Qingling
Q
Strieter
Robert M
RM
Adegboyega
Patrick A
PA
Aw
Tak Yee
TY
D000256:Adenoviridae / Q000502:physiology*; D000257:Adenoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D000818:Animals; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy; D008099:Liver / Q000276:immunology / Q000473:pathology* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000821:virology
D018946:Chemokine CCL5