Healthy lung development hinges on immune-epithelial crosstalk, revealing a new role for immune cells outside of immunity, with implications for treating respiratory diseases.

Immune cells play an active and intimate role in directing the growth of human lung tissue during development, researchers find, furthering the understanding of early lung development and the role of immune cells outside of immunity.

The research, published in Science Immunology, offers new insights for understanding and treating respiratory conditions, such as chronic obstructive pulmonary disease (COPD). 

The work reveals a “surprising” coordination between the immune and respiratory systems, much earlier in development than previously thought, according to the researchers from the Wellcome Sanger Institute, University College London (UCL), and their collaborators at European Molecular Biology Laboratory’s European Bioinformatics Institute. This discovery raises questions about the potential role of immune cells in other developing organs across the body.

The researchers used advanced single-cell technologies to map the development of early human lung immune cells over time, creating an immune cell atlas of the developing lung. It is part of the international Human Cell Atlas initiative, which entails mapping every cell type in the human body to better our understanding of health, infection, and disease.

Immune cells make up a substantial portion of the airways and mature lungs, which have critical gas exchange and barrier functions, providing protection against infection of the respiratory tract. However, the roles of immune cells in the developing organ have remained unexplored compared to structural or lining cell types. Recent discoveries confirm the presence of immune cells in human lungs as early as five weeks into development.

To explore whether the immune system might influence how lungs grow, the team studied immune cells in early human lungs from fivr to 22 weeks of development. They used various techniques, including single-cell sequencing and experiments with lung cell cultures, to see if immune cells could affect lung cell development.

They identified key regulators of lung development, including signaling molecules IL-1β and IL-13 that facilitate the coordination of lung stem cells differentiating into specialized mature cell types.

The researchers detected an infiltration of innate, followed by adaptive immune cells. Innate cells included innate lymphoid cells, natural killer cells, myeloid cells, and progenitor cells. With respect to adaptive immune cells, as well as T cells, both developing and mature B lineage cells were detected, indicating that the lung environment supports B cell development.

The researchers say the findings fundamentally change the understanding of the immune and epithelial interactions that are crucial for fetal lung maturation. They also suggest that early immune disturbances could manifest as pediatric lung disease.

These new insights into mechanisms in early lung formation will also contribute to the development of new therapeutic approaches for regenerating damaged lung tissue and restoring lung function, the researchers say. 

“We now know immune-epithelial crosstalk is a feature of early lung development. This vital baseline of healthy lung development will help us understand what happens when lung developmental processes get disrupted, for example in preterm births, which can lead to respiratory deficiencies,” says Marko Nikolić, PhD, senior author of the study at UCL Division of Medicine and honorary consultant in respiratory medicine, in a release.

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