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 disease1,2,3,4,5,6,7,8. The neonatal immune system matures during this period9, 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 colonization10 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.

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Figure 1: Neonatal mice develop exaggerated allergic airway inflammation after exposure to HDM.
Figure 2: PD-L1 is transiently expressed on CD11b+ DCs in the lung.
Figure 3: The microbiota promotes transient PD-L1 expression and induces Treg cells in the lung.
Figure 4: Blockade of PD-L1 activity during the neonatal period maintains the exaggerated responsiveness to HDM through adulthood.

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Acknowledgements

This work is supported by the Leenaards Foundation in Lausanne and the Swiss National Science Foundation grant 310030_146983, awarded to B.J.M. B.J.M. is a Cloetta Medical Research Fellow and, by holding this title, receives financial support. B.J.M. and C.M.L. are part of the European Cooperation in Science and Technology Action BM1201, Developmental Origins of Chronic Lung Disease. S.S. and C.M.L. are supported by the Wellcome Trust grants 087618/Z/08/Z and 083586/Z/07/Z. C.M.L. is a Wellcome Senior Fellow in Basic Biomedical Science and, by holding this title, receives financial support. We thank D. Pinschewer and S. Kallert for valuable discussions and critical feedback.

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B.J.M. conceived the study. B.J.M. and E.S.G. designed the study. E.S.G., A.T. and K.Y. performed experiments. S.S. and R.S. performed neonatal lung function experiments. K.D.M. provided germ-free mice. E.S.G., A.T., K.Y., S.S., C.M.L., L.P.N. and B.J.M. provided critical analysis and discussion. E.S.G. and B.J.M. wrote the paper.

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Correspondence to Benjamin J Marsland.

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The authors declare no competing financial interests.

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Gollwitzer, E., Saglani, S., Trompette, A. et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat Med 20, 642–647 (2014). https://doi.org/10.1038/nm.3568

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