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 Cuív & 6 others Ping Zhang, Ashraful Haque, Geoffrey R. Hill, Peter D. Sly, John W. Upham, Simon Phipps

Research output: Contribution to journalArticle

10 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

Viral Bronchiolitis
Semaphorins
Bronchiolitis
Dendritic Cells
Asthma
Propionates
Pneumovirus Infections
Neuropilin-1
Respiratory Syncytial Viruses
Microbiota
Viral Load
Nose
Interferons
Newborn Infant
Anti-Bacterial Agents
Therapeutics

Cite this

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 ; Cuív, Páraic ; Zhang, Ping ; Haque, Ashraful ; Hill, Geoffrey R. ; Sly, Peter D. ; Upham, John W. ; Phipps, Simon. / Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion. In: Journal of Experimental Medicine. 2018 ; Vol. 215, No. 2. pp. 537-557.
@article{7a54140caf574710b5a623ae86c1d4af,
title = "Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion",
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.",
author = "Lynch, {Jason P.} and Werder, {Rhiannon B.} and Zhixuan Loh and Sikder, {Md Al Amin} and Bodie Curren and Vivian Zhang and Rogers, {Matthew J.} and Katie Lane and Jennifer Simpson and Mazzone, {Stuart B.} and Kirsten Spann and John Hayball and Kerrilyn Diener and Everard, {Mark L.} and Blyth, {Christopher C.} and Christian Forstner and Dennis, {Paul G.} and Nida Murtaza and Mark Morrison and P{\'a}raic Cu{\'i}v and Ping Zhang and Ashraful Haque and Hill, {Geoffrey R.} and Sly, {Peter D.} and Upham, {John W.} and Simon Phipps",
year = "2018",
month = "2",
day = "1",
doi = "10.1084/jem.20170298",
language = "English",
volume = "215",
pages = "537--557",
journal = "The Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "The Rockefeller University Press",
number = "2",

}

Lynch, JP, Werder, RB, Loh, Z, Sikder, MAA, Curren, B, Zhang, V, Rogers, MJ, Lane, K, Simpson, J, Mazzone, SB, Spann, K, Hayball, J, Diener, K, Everard, ML, Blyth, CC, Forstner, C, Dennis, PG, Murtaza, N, Morrison, M, Cuív, P, Zhang, P, Haque, A, Hill, GR, Sly, PD, Upham, JW & Phipps, S 2018, 'Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion' Journal of Experimental Medicine, vol. 215, no. 2, pp. 537-557. https://doi.org/10.1084/jem.20170298

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; Cuív, Páraic; Zhang, Ping; Haque, Ashraful; Hill, Geoffrey R.; Sly, Peter D.; Upham, John W.; Phipps, Simon.

In: Journal of Experimental Medicine, Vol. 215, No. 2, 01.02.2018, p. 537-557.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Plasmacytoid dendritic cells protect from viral bronchiolitis and asthma through semaphorin 4a-mediated T reg expansion

AU - Lynch, Jason P.

AU - Werder, Rhiannon B.

AU - Loh, Zhixuan

AU - Sikder, Md Al Amin

AU - Curren, Bodie

AU - Zhang, Vivian

AU - Rogers, Matthew J.

AU - Lane, Katie

AU - Simpson, Jennifer

AU - Mazzone, Stuart B.

AU - Spann, Kirsten

AU - Hayball, John

AU - Diener, Kerrilyn

AU - Everard, Mark L.

AU - Blyth, Christopher C.

AU - Forstner, Christian

AU - Dennis, Paul G.

AU - Murtaza, Nida

AU - Morrison, Mark

AU - Cuív, Páraic

AU - Zhang, Ping

AU - Haque, Ashraful

AU - Hill, Geoffrey R.

AU - Sly, Peter D.

AU - Upham, John W.

AU - Phipps, Simon

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85041423642&partnerID=8YFLogxK

U2 - 10.1084/jem.20170298

DO - 10.1084/jem.20170298

M3 - Article

VL - 215

SP - 537

EP - 557

JO - The Journal of Experimental Medicine

JF - The Journal of Experimental Medicine

SN - 0022-1007

IS - 2

ER -