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

Author:

Lynch Jason P.1234ORCID,Werder Rhiannon B.14ORCID,Loh Zhixuan15,Sikder Md. Al Amin14ORCID,Curren Bodie14,Zhang Vivian14,Rogers Matthew J.1ORCID,Lane Katie1,Simpson Jennifer14,Mazzone Stuart B.16,Spann Kirsten78ORCID,Hayball John910,Diener Kerrilyn910,Everard Mark L.11ORCID,Blyth Christopher C.11121314,Forstner Christian15,Dennis Paul G.15,Murtaza Nida16,Morrison Mark16,Ó Cuív Páraic16,Zhang Ping4,Haque Ashraful174ORCID,Hill Geoffrey R.174,Sly Peter D.1718ORCID,Upham John W.16ORCID,Phipps Simon1174ORCID

Affiliation:

1. School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland, Australia

2. Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Cambridge, MA

3. Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA

4. QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia

5. The Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, Australia

6. Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne, Victoria, Australia

7. School of Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia

8. Institute of Health and Biomedical Science, Queensland University of Technology, Brisbane, Queensland, Australia

9. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia

10. Robinson Research Institute, Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia

11. School of Medicine, University of Western Australia, Perth, Western Australia, Australia

12. Department of Infectious Diseases, Princess Margaret Hospital for Children, Perth, Western Australia, Australia

13. Department of Microbiology, PathWest Laboratory Medicine WA, Princess Margaret Hospital for Children, Perth, Western Australia, Australia

14. Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia

15. School of Earth and Environmental Sciences, The University of Queensland, St. Lucia, Queensland, Australia

16. The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia

17. Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, Queensland, Australia

18. Child Health Research Centre, The University of Queensland, St. Lucia, Queensland, Australia

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.

Funder

National Health and Medical Research Council

Australian Research Council

Australian Infectious Diseases Research Centre

University of Queensland

Rebecca L. Cooper Medical Research Foundation

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Cited by 65 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3