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.

B Cell–Intrinsic MyD88 Signaling Is Essential for IgE Responses in Lungs Exposed to Pollen Allergens

“…These differences could be explained by the unique immune system present in the lungs. Although healthy lungs were previously regarded as a sterile environment, accumulating evidence demonstrated the presence of a microbiome in lungs and its association with lung diseases (60,61). Thus, lungs may have a distinct immune system reminiscent of that in the intestine or skin.…”

Perinatal Activation of the Interleukin-33 Pathway Promotes Type 2 Immunity in the Developing Lung

“…(legend continued on next page) ( Figure 3A). A small number of studies have described increased numbers of CD11b + DCs in neonatal lungs (Gollwitzer et al, 2014;Roux et al, 2011), but a careful distinction between CD11b + cDCs and moDCs has never been made. Using a panel that discriminates cDCs from monocyte-derived DCs , we found that CD11b + CD64 + moDCs represented the largest DC subset in the lung from E20 until PND2 ( Figure 3B).…”

“…In support, the spontaneous wave of type 2 immunity around PND14 was intact in Rag2-deficient mice, and ILC2 accumulations were even enhanced in these mice, most likely due to increased availability of IL-2 in Rag2 À/À mice. Studies in neonatal rodents and humans reported scarcity as well as immaturity of pulmonary DCs, hyporesponsiveness to PAMPs, and low lymphocyte numbers and therefore suggested incompetence of the early postnatal pulmonary immune system to mount adaptive immune responses, an effect that was even exacerbated in germ-free mice (Belderbos et al, 2009;Gollwitzer et al, 2014;Nelson and Holt, 1995;Nelson et al, 1994;Roux et al, 2011;Tschernig et al, 2006). In accordance with these studies, we found that DCs were indeed severely impaired in neonatal lungs, and the few CD11b + DCs in neonatal lungs during the first post-natal week were sessile CD11b + CD64 + moDCs that closely resemble macrophages Plantinga et al, 2013).…”

İnsan Mikrobiyomu: Beslenme ve Sağlık Üzerindeki Etkileri

“…Bağırsak mikrobiyotası da bağırsak fonksiyonlarının gelişimini şekillendirir. Bu bağırsak fonksiyonlardaki farklılıklar da karşılaşılan virüs ve alerjenlere karşı yanıtın yoğunluk ve içeriğini etkiler [34,35]. Bu konuda farklı bir görüş ise solunum sisteminin mikrobiyel kolonizasyon için biraz daha fazla uygun bir yer olduğu yönündedir.…”