CXCL10/CXCR3-mediated responses promote immunity to respiratory syncytial virus infection by augmenting dendritic cell and CD8(+) T cell efficacy.
The induction of inflammatory cytokines during respiratory viral infections contributes to both disease pathogenesis and resolution. The present studies investigated the role of the chemokine CXCL10 and its specific receptor, CXCR3, in the host response to pulmonary respiratory syncytial virus (RSV) infection. Antibody-mediated neutralization of CXCL10 resulted in a significant increase in disease pathogenesis, including airway hyperresponsiveness (AHR), mucus gene expression, and impaired viral clearance. When the pulmonary cytokine levels were examined, only type I IFN and IL-12p70 were significantly reduced. These latter observations were reflected in reduced dendritic cell (DC) numbers and DC maturation in the lungs of RSV-infected mice treated with anti-CXCL10. Neutralization of the only known receptor for CXCL10, CXCR3, resulted in similar increases in pathogenic responses. When bone marrow-derived DC were incubated with CXCL10 and RSV, an up-regulation of type I IFN was observed. In addition, T lymphocytes were also examined and a significant decrease in the number of RSV M2 peptide-specific CD8(+) T cells was identified. These findings highlight a previously unappreciated role for the CXCL10:CXCR3 signaling axis in RSV-infected animals by recruiting virus-specific T cells into the lung and promoting viral clearance.
Lindell
Dennis M
DM
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA. denmklin@umich.edu <denmklin@umich.edu>
Lane
Thomas E
TE
Lukacs
Nicholas W
NW
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D054357:Chemokine CXCL10 / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005260:Female; D008168:Lung / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology; D014779:Virus Replication
D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3