CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC.
Chemokines are important mediators of the immune response to pathogens, but can also promote chronic inflammatory states. Chemokine receptor 6 (CCR6) is found on immature DC and effector/memory T cells, and binds a single ligand, CCL20, with high affinity. Here, we investigated the role of CCL20 and CCR6 in a pulmonary viral infection caused by RSV, a ubiquitous virus that can cause severe pulmonary complications. Neutralization of CCL20 during RSV infection significantly reduced lung pathology and favored a Th1 effector response. CCR6-deficient animals recapitulated this phenotype, and additionally showed enhanced viral clearance when compared with WT mice. No differences were observed in migration of T cells to the lungs of CCR6(-/-) animals; however, a significant reduction was observed in numbers of conventional DC (cDC), but not plasmacytoid DC, in CCR6(-/-) mice. A pathogenic phenotype could be reconstituted in CCR6(-/-) mice by supplying cDC into the airway, indicating that mere number of cDC dictates the adverse response. Our data suggest that blockade of the CCL20/CCR6 pathway provides an environment whereby the attenuated recruitment of cDC alters the balance of innate immune cells and mediates the efficient antiviral response to RSV.
Kallal
Lara E
LE
Department of Molecular & Cellular Pathology, The University of Michigan, Ann Arbor, MI 48109, USA. lkkelley@umich.edu
Schaller
Matthew A
MA
Lindell
Dennis M
DM
Lira
Sergio A
SA
Lukacs
Nicholas W
NW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D016535:Bronchial Hyperreactivity / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D002478:Cells, Cultured / Q000276:immunology / Q000637:transplantation; D054418:Chemokine CCL20 / Q000037:antagonists & inhibitors / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D018928:Immunity, Mucosal / Q000276:immunology*; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011024:Pneumonia, Viral / Q000276:immunology* / Q000473:pathology / Q000821:virology; D054399:Receptors, CCR6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D000911:Antibodies, Monoclonal; C493447:CCL20 protein, mouse; C498126:CCR6 protein, mouse; D054418:Chemokine CCL20; D054399:Receptors, CCR6; D007371:Interferon-gamma