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

Lynch, Jason P., Werder, Rhiannon B., Loh, Zhixuan, Sikder, Md Al Amin, Curren, Bodie, Zhang, Vivian, Rogers, Matthew J. , Lane, Katie, Simpson, Jennifer, Mazzone, Stuart B., Spann, Kirsten, Hayball, John, Diener, Kerrilyn, Everard, Mark L., Blyth, Christopher C., Forstner, Christian, Dennis, Paul G., Murtaza, Nida, Morrison, Mark, Ó Cuív, Páraic, Zhang, Ping, Haque, Ashraful, Hill, Geoffrey R., Sly, Peter D., Upham, John W. and Phipps, Simon (2017) Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion. The Journal of Experimental Medicine, 215 2: 537-557. doi:10.1084/jem.20170298

Author Lynch, Jason P.
Werder, Rhiannon B.
Loh, Zhixuan
Sikder, Md Al Amin
Curren, Bodie
Zhang, Vivian
Rogers, Matthew J. 
Lane, Katie
Simpson, Jennifer
Mazzone, Stuart B.
Spann, Kirsten
Hayball, John
Diener, Kerrilyn
Everard, Mark L.
Blyth, Christopher C.
Forstner, Christian
Dennis, Paul G.
Murtaza, Nida
Morrison, Mark
Ó Cuív, Páraic
Zhang, Ping
Haque, Ashraful
Hill, Geoffrey R.
Sly, Peter D.
Upham, John W.
Phipps, Simon
Title Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion
Journal name The Journal of Experimental Medicine   Check publisher's open access policy
ISSN 1540-9538
Publication date 2017-12-22
Year available 2017
Sub-type Article (original research)
DOI 10.1084/jem.20170298
Open Access Status Not yet assessed
Volume 215
Issue 2
Start page 537
End page 557
Total pages 21
Place of publication New York, NY United States
Publisher Rockefeller University Press
Language eng
Subject 2723 Immunology and Allergy
2403 Immunology
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.
Keyword Respiratory Syncytial Virus
Pneumovirus Infection
Childhood Asthma
Nasopharyngeal Microbiome
Cytokine Responses
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 1023756
Institutional Status UQ

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Created: Wed, 27 Dec 2017, 12:03:29 EST