CCL20/CCR6 blockade enhances immunity to RSV by impairing recruitment of DC

Eur J Immunol. 2010 Apr;40(4):1042-52. doi: 10.1002/eji.200939778.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • Bronchial Hyperreactivity / etiology
  • Bronchial Hyperreactivity / immunology
  • Bronchial Hyperreactivity / prevention & control
  • Cells, Cultured / immunology
  • Cells, Cultured / transplantation
  • Chemokine CCL20 / antagonists & inhibitors
  • Chemokine CCL20 / physiology*
  • Chemotaxis, Leukocyte*
  • Coculture Techniques
  • Dendritic Cells / immunology*
  • Dendritic Cells / transplantation
  • Immunity, Mucosal / immunology*
  • Immunotherapy, Adoptive
  • Interferon-gamma / biosynthesis
  • Lung / immunology
  • Lung / pathology
  • Lung / virology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Pneumonia, Viral / immunology*
  • Pneumonia, Viral / pathology
  • Pneumonia, Viral / virology
  • Receptors, CCR6 / deficiency
  • Receptors, CCR6 / genetics
  • Receptors, CCR6 / physiology*
  • Respiratory Syncytial Virus Infections / immunology*
  • Respiratory Syncytial Virus Infections / pathology
  • Respiratory Syncytial Viruses / immunology*
  • Th1 Cells / immunology
  • Th2 Cells / immunology

Substances

  • Antibodies, Monoclonal
  • CCL20 protein, mouse
  • CCR6 protein, mouse
  • Chemokine CCL20
  • Receptors, CCR6
  • Interferon-gamma