title: Lung microbiota promotes tolerance to allergens in neonates via PD-L1.
abstract: Epidemiological data point toward a critical period in early life during which environmental cues can set an individual on a trajectory toward respiratory health or disease. The neonatal immune system matures during this period, although little is known about the signals that lead to its maturation. Here we report that the formation of the lung microbiota is a key parameter in this process. Immediately following birth, neonatal mice were prone to develop exaggerated airway eosinophilia, release type 2 helper T cell cytokines and exhibit airway hyper-responsiveness following exposure to house dust mite allergens, even though their lungs harbored high numbers of natural CD4(+)Foxp3(+)CD25(+)Helios(+) regulatory T (Treg) cells. During the first 2 weeks after birth, the bacterial load in the lungs increased, and representation of the bacterial phyla shifts from a predominance of Gammaproteobacteria and Firmicutes towards Bacteroidetes. The changes in the microbiota were associated with decreased aeroallergen responsiveness and the emergence of a Helios(-) Treg cell subset that required interaction with programmed death ligand 1 (PD-L1) for development. Absence of microbial colonization(10) or blockade of PD-L1 during the first 2 weeks postpartum maintained exaggerated responsiveness to allergens through to adulthood. Adoptive transfer of Treg cells from adult mice to neonates before aeroallergen exposure ameliorated disease. Thus, formation of the airway microbiota induces regulatory cells early in life, which, when dysregulated, can lead to sustained susceptibility to allergic airway inflammation in adulthood.
authors.affiliation: Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, BH19.206 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Eva S
authors.initials: ES
authors.lastname: Gollwitzer
authors.affiliation: Leukocyte Biology, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London, United Kingdom.
authors.forename: Sejal
authors.initials: S
authors.lastname: Saglani
authors.affiliation: Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, BH19.206 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Trompette
authors.affiliation: Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, BH19.206 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Koshika
authors.initials: K
authors.lastname: Yadava
authors.affiliation: Leukocyte Biology, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London, United Kingdom.
authors.forename: Rebekah
authors.initials: R
authors.lastname: Sherburn
authors.affiliation: Maurice Müller Laboratories, University Clinic for Visceral Surgery and Medicine, University of Bern, Bern, Switzerland.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: McCoy
authors.affiliation: Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, BH19.206 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Nicod
authors.affiliation: Leukocyte Biology, National Heart and Lung Institute, Faculty of Medicine, Imperial College, London, United Kingdom.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Lloyd
authors.affiliation: Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, BH19.206 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Benjamin J
authors.identifier: 0000000314573160
authors.initials: BJ
authors.lastname: Marsland
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology*; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology / Q000382:microbiology*; D060890:B7-H1 Antigen / Q000276:immunology*; D001985:Bronchial Provocation Tests; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D064307:Microbiota / Q000276:immunology*; D039981:Pyroglyphidae / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000485:Allergens; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; D017931:DNA Primers