Poster Presentation The Australasian Society for Immunology 2017 Annual Scientific Meeting

pDCs or microbial metabolites induce sema4a-mediated treg cell expansion to protect against severe viral bronchiolitis and subsequent asthma (#370)

Md. Al Amin Sikder 1 2 , Jason Lynch 1 2 , Rhiannon Werder 1 2 , Bodie Curren 1 , Matthew Rogers 2 , Katie Lane 2 , Zhixuan Loh 2 , Kerri Diener 3 , John Hayball 3 , Geoffrey Hill 1 , Ashraful Haque 1 , Stuart Mazzone 2 , Paraic O Cuiv 4 , Mark Morrison 4 , Kirsten Spann 5 , John Upham 4 , Simon Phipps 1 2
  1. QIMR Berghofer Medical Research, Herston, Brisbane, Queensland, Australia
  2. School of Biomedical Sciences, University of Queensland, QLD, Australia, St. Lucia, QUEENSLAND, Australia
  3. School of Pharmacy and Medical Sciences, The University of South Adelaide, South Adelaide, SA, Australia
  4. Diamantina Institute, University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
  5. School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia

Abstract

RSV-bronchiolitis in infancy is a major independent risk factor for subsequent asthma but the causal mechanisms remain obscure. We modelled this association in neonatal mice, and identified that transient plasmacytoid dendritic cell (pDC) depletion during primary Pneumoviral infection alone was sufficient to predispose to severe bronchiolitis in early-life and progression to asthma following re-infection in adulthood. pDC depletion ablated type I and III IFN production and increased viral load, however the heightened immunopathology and induction of type-2 inflammation stemmed from a failure to expand functional neuropilin-1+ regulatory T (Treg) cells, which were dependent on pDC-derived semaphorin 4a (Sema4a). In adult mice, pDC depletion perturbed Treg cell expansion and predisposed to severe bronchiolitis but only after antibiotic treatment, implicating a protective role of the microbiome. Conversely, treatment of pDC-depleted neonates with the microbial-derived metabolite propionate restored Treg cell expansion and function in a Sema4a-dependent manner, ameliorating bronchiolitis severity and subsequent asthma. Nasal propionate levels were also lower in 2-year-old children with viral bronchiolitis and correlated with an IL-6high IL-10low cytokine microenvironment. Our findings highlight a common but age-related Sema4a-mediated pathway by which pDC and microbial colonization induce Treg cell expansion to confer protection against severe bronchiolitis and subsequent asthma.