Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/114104
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Type: Journal article
Title: Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion
Author: Lynch, J.
Werder, R.
Loh, Z.
Sikder, M.
Curren, B.
Zhang, V.
Rogers, M.
Lane, K.
Simpson, J.
Mazzone, S.
Spann, K.
Hayball, J.
Diener, K.
Everard, M.
Blyth, C.
Forstner, C.
Dennis, P.
Murtaza, N.
Morrison, M.
Cuív, P.
et al.
Citation: Journal of Experimental Medicine, 2018; 215(2):537-557
Publisher: Rockefeller University Press
Issue Date: 2018
ISSN: 0022-1007
1540-9538
Statement of
Responsibility: 
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 Ó Cuív, Ping Zhang, Ashraful Haque, Geoffrey R. Hill, Peter D. Sly, John W. Upham, and Simon Phipps
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.
Keywords: Dendritic Cells; Animals; Mice, Inbred C57BL; Animals, Newborn; Mice, Transgenic; Humans; Mice; Bronchiolitis, Viral; Respiratory Syncytial Virus Infections; Asthma; Disease Models, Animal; Fatty Acids, Volatile; Semaphorins; Interleukin-10; Child; Child, Preschool; Female; Male; T-Lymphocytes, Regulatory; Receptor, Interferon alpha-beta; Microbiota
Rights: © 2018 Lynch et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
RMID: 0030082261
DOI: 10.1084/jem.20170298
Grant ID: http://purl.org/au-research/grants/nhmrc/1023756
http://purl.org/au-research/grants/arc/FT130100518
Appears in Collections:Microbiology and Immunology publications

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