Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion.
Jason P LynchRhiannon B WerderZhixuan LohMd Al Amin SikderBodie CurrenVivian ZhangMatthew J RogersKatie LaneJennifer SimpsonStuart B MazzoneKirsten M SpannJohn HayballKerrilyn DienerMark L EverardChristopher C BlythChristian ForstnerPaul G DennisNida MurtazaMark MorrisonPáraic Ó CuívPing ZhangAshraful HaqueGeoffrey R HillPeter D SlyJohn W UphamSimon PhippsPublished in: The Journal of experimental medicine (2017)
Respiratory syncytial virus-bronchiolitis is a major independent risk factor for subsequent asthma, but the causal mechanisms remain obscure. We identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumovirus infection alone predisposed to severe bronchiolitis in early life and subsequent asthma in later life after reinfection. pDC depletion ablated interferon production and increased viral load; however, the heightened immunopathology and susceptibility to subsequent asthma stemmed from a failure to expand functional neuropilin-1+ regulatory T (T reg) cells in the absence of pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion predisposed to severe bronchiolitis only after antibiotic treatment. Consistent with a protective role for the microbiome, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate promoted Sema4a-dependent T reg cell expansion, ameliorating both diseases. In children with viral bronchiolitis, nasal propionate levels were decreased and correlated with an IL-6high/IL-10low microenvironment. We highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to protect against severe bronchiolitis and subsequent asthma.
Keyphrases
- dendritic cells
- respiratory syncytial virus
- chronic obstructive pulmonary disease
- lung function
- immune response
- regulatory t cells
- allergic rhinitis
- early life
- single cell
- cell therapy
- early onset
- stem cells
- young adults
- type diabetes
- induced apoptosis
- metabolic syndrome
- preterm infants
- cell proliferation
- low birth weight
- signaling pathway
- mesenchymal stem cells
- subarachnoid hemorrhage
- cerebral ischemia