title: IL-4Rα on dendritic cells in neonates and Th2 immunopathology in respiratory syncytial virus infection.
abstract: Respiratory syncytial virus (RSV) is one of the leading causes of bronchiolitis in children, and severe RSV infection early in life has been associated with asthma development. Using a neonatal mouse model, we have shown that down-regulation of IL-4 receptor α (IL-4Rα) with antisense oligonucleotides in the lung during neonatal infection protected from RSV immunopathophysiology. Significant down-regulation of IL-4Rα was observed on pulmonary CD11b+myeloid dendritic cells (mDCs) suggesting a role for IL-4Rα on mDCs in the immunopathogenesis of neonatal RSV infection. Here, we demonstrated that neonatal CD11b+mDCs expressed higher levels of IL-4Rα than their adult counterparts. Because CD11b+mDCs mainly present antigens to CD4+T cells, we hypothesized that increased expression of IL-4Rα on neonatal CD11b+mDCs was responsible for Th2 - biased RSV immunopathophysiology. Indeed, when IL-4Rα was selectively deleted from CD11b+mDCs, the immunopathophysiology typically observed following RSV reinfection was ablated, including Th2 inflammation, airway-mucus hyperproduction, and pulmonary dysfunction. Further, overexpression of IL-4Rα on adult CD11b+DCs and their adoptive transfer into adult mice was able to recapitulate the Th2-biased RSV immunopathology typically observed only in neonates infected with RSV. IL-4Rα levels on CD11c+cells were inversely correlated with maturation status of CD11b+mDCs upon RSV infection. Our data demonstrate that developmentally regulated IL-4Rα expression is critical for the maturity of pulmonary CD11b+mDCs and the Th2-biased immunopathogenesis of neonatal RSV infection.
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.|Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.
authors.forename: Bishwas
authors.initials: B
authors.lastname: Shrestha
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: Dahui
authors.initials: D
authors.lastname: You
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: Jordy
authors.initials: J
authors.lastname: Saravia
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Siefker
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: Sridhar
authors.initials: S
authors.lastname: Jaligama
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: Greg I
authors.initials: GI
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
authors.forename: Asmaa A
authors.initials: AA
authors.lastname: Sallam
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.|Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Harding
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and scormier@uthsc.edu.|Children's Foundation Research Institute, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.|Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee, USA; and.
authors.forename: Stephania A
authors.initials: SA
authors.lastname: Cormier
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D018357:Respiratory Syncytial Virus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D012136:Respiratory Syncytial Viruses / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D039481:CD11b Antigen; D011956:Receptors, Cell Surface; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit
keywords: CD11b+ mDCs; RSV; immunopathogenesis