An international research group has combined advanced single-cell technologies with studies in lung organoids to map the development of early human lung immune cells over time. Their results, which outline how such cells play an active and intimate role in directing the growth of human lung tissue during development, reveal a surprising coordination between the immune and respiratory systems, much earlier in development than previously thought.

This study has created a first-of-its-kind immune cell atlas of the developing lung. It is part of the international Human Cell Atlas initiative, which is mapping every cell type in the human body, to transform our understanding of health, infection, and disease. The new findings, the team said, revolutionize our understanding of early lung development and the role of immune cells outside of immunity. The results also offer new insights into our understanding and potential treatment of respiratory conditions, such as chronic obstructive pulmonary disease (COPD), and will help to shed light on the mechanisms behind childhood lung diseases. The discoveries raise additional questions about the potential role of immune cells in other developing organs across the body.

Kerstin Meyer, PhD, at the Wellcome Sanger Institute, commented, “The active participation of immune cells expands the possibilities for understanding and addressing impaired lung formation. What is super exciting about this mechanism is that it may well apply in other organ systems too.” Meyer is co-senior author of the team’s published paper in Science Immunology, titled “Early human lung immune cell development and its role in epithelial cell fate.”

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. “Adult human lungs are composed of approximately 20% immune cells,” the team wrote, “known to play a crucial role in both normal lung homeostasis and pathogenesis, which suggests potential analogous functions during development.”

Recent discoveries confirm the presence of immune cells in human lungs as early as five weeks post-conception. However, the exact roles of immune cells in the developing organ have remained unexplored compared to studies examining structural or lining cell types. “Studies of human lung development have focused on epithelial and mesenchymal cell types and function, but much less is known about the developing lung immune cells, even though the airways are a major site of mucosal immunity after birth,” the team continued.

To explore whether the immune system might influence how lungs grow, the team studied immune cells in early human lungs from 5 to 22 weeks of development. They used various techniques, including single-cell sequencing, to see if immune cells could affect lung cell development. “To explore the establishment of the immune system and its possible role in directing lung development, we profiled the immune cells present in early human lungs from 5 to 22 pcw using a combination of single-cell RNA sequencing (scRNA-seq), CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing), B cell receptor (BCR) and T cell receptor (TCR) sequencing, immunohistochemistry (IHC), and flow cytometry.” The researchers combined their genetic and molecular techniques with studies in 3D lung epithelial organoid cultures derived from human embryonic lungs.

The researchers detected an infiltration of innate, followed by adaptive immune cells. Innate cells included innate lymphoid cells (ILCs), natural killer (NK) 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. The team noted, “Our data suggest that the fetal lung microenvironment supports the full spectrum of B lymphocyte differentiation.” The studies also identified key regulators of lung development, including the cytokine signaling molecules IL-1β and IL-13 that facilitate the coordination of lung stem cells differentiating into specialized mature cell types.

The study findings indicated that IL-1β produced by immune cells directly induced airway epithelial progenitor cells to differentiate into mature lung lining cells, by decreasing SOX9 expression and proliferation, driving lung epithelial progenitor cells to stop self-renewal. “… we demonstrate that IL-1β decreases SOX9 expression and proliferation, resulting in airway differentiation,” they wrote. “We found that IL-1β drives epithelial progenitor exit from self-renewal and differentiation to basal cells in vitro. In vivo, IL-1β–producing myeloid cells were found throughout the lung and adjacent to epithelial tips, suggesting that immune cells may direct human lung epithelial development.”

The collective results 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. Respiratory conditions account for almost 20% of all deaths in children under five years worldwide.

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. In their report, the authors suggested that while their functional analyses were focused on the role of cytokines in early epithelial development, their study “… charts the presence of a complex and highly dynamic lung immune compartment, providing an important resource for the scientific community on which to base future functional studies to examine the interplay of the immune compartment with endothelial, epithelial, and mesenchymal cells.”

Co-senior study author Marko Nikolić, PhD, at UCL Division of Medicine and honorary consultant in respiratory medicine, said, “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.”

Added Wellcome Sanger Institute co-senior study author and Human Cell Atlas co-founder Sarah Teichmann, PhD, “If we are to fully understand the root causes of disease, we require a complete view of cells at all stages in the human body. This important contribution towards a comprehensive Human Cell Atlas will be a valuable reference for studying lung diseases.”

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