Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion

Jason P. Lynch, Rhiannon B. Werder, Zhixuan Loh, Md Al Amin Sikder, Bodie Curren, Vivian Zhang, Matthew J. Rogers, Katie Lane, Jennifer Simpson, Stuart B. Mazzone, Kirsten Spann, John Hayball, Kerrilyn Diener, Mark L. Everard, Christopher C. Blyth, Christian Forstner, Paul G. Dennis, Nida Murtaza, Mark Morrison, Páraic CuívPing Zhang, Ashraful Haque, Geoffrey R. Hill, Peter D. Sly, John W. Upham, Simon Phipps

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)537-557
Number of pages21
JournalJournal of Experimental Medicine
Volume215
Issue number2
DOIs
Publication statusPublished - 1 Feb 2018

Fingerprint Dive into the research topics of 'Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion'. Together they form a unique fingerprint.

Cite this