Immune cells shape lung before birth and provide new avenues for treating respiratory diseases

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

The research offers new insights for understanding and treating respiratory conditions, such as chronic obstructive pulmonary disease (COPD). Respiratory conditions account for almost 20 per cent of all deaths in children under five years worldwide¹.

The work reveals a surprising coordination between the immune and respiratory systems, much earlier in development than previously thought. This discovery raises questions about the potential role of immune cells in other developing organs across the body.

Researchers from the Wellcome Sanger Institute, University College London (UCL) and their collaborators at EMBL’s European Bioinformatics Institute used advanced single-cell technologies to map the development of early human lung immune cells over time.

This study has created a first-of-its-kind immune cell atlas of the developing lung². It is part of the international Human Cell Atlas³ initiative, which is mapping every cell type in the human body, to transform our understanding of health, infection and disease.

The findings, published today (15 December) in Science Immunology, will help shed light on the mechanisms behind childhood lung diseases.

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 development⁴.

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 and experiments with lung cell cultures, to see if immune cells could affect lung cell development.

They identified key regulators of lung development, including signalling molecule IL-1β and IL-13 that facilitate the coordination of lung stem cells differentiating into specialised mature cell types⁵.

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, indicating that the lung environment supports B cell development.

The findings fundamentally change the understanding of the immune and epithelial interactions that are crucial for foetal lung maturation. They also suggest that early immune disturbances could manifest as paediatric 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.

Dr Peng He and Dr Jo Barnes, co-first authors of the study at the Wellcome Sanger Institute and EMBL’s European Bioinformatics Institute, and UCL Division of Medicine respectively, said: “By adopting a focused strategy in mapping the immune system, we reveal a symbiotic relationship between immune cells and developing lungs. These detailed insights open the door to potential regenerative therapies in not only the lung, but in other vital human organs.”

Dr Marko Nikolić, senior author of the study 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.”

Dr Kerstin Meyer, senior author of the study at the Wellcome Sanger Institute, said: “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.”

Dr Sarah Teichmann, senior author of the study at the Wellcome Sanger Institute and Co-founder of the Human Cell Atlas, said: “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.”

ENDS

Contact details:
Jelena Pupavac
Press Office
Wellcome Sanger Institute
Cambridge, CB10 1SA
Email: press.office@sanger.ac.uk

Notes to Editors:

1. https://www.who.int/data/gho/indicator-metadata-registry/imr-details/3147
2. The researchers analysed human embryonic and foetal lung tissue between 5 and 22 weeks post-conception. Human embryonic tissue was provided by the Joint MRC/Wellcome Trust Human Developmental Biology Resource (www.hdbr.org)
3. The Human Cell Atlas (HCA) is an international collaborative consortium which is creating comprehensive reference maps of all human cells—the fundamental units of life—as a basis for understanding human health and for diagnosing, monitoring, and treating disease. The HCA is likely to impact every aspect of biology and medicine, propelling translational discoveries and applications and ultimately leading to a new era of precision medicine.
   The HCA was co-founded in 2016 by Dr Sarah Teichmann at the Wellcome Sanger Institute (UK) and Dr Aviv Regev, then at the Broad Institute of MIT and Harvard (USA). A truly global initiative, there are now more than 3,100 HCA members, from 98 countries around the world. https://www.humancellatlas.org
4. https://www.cell.com/cell/fulltext/S0092-8674(22)01415-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867422014155%3Fshowall%3Dtrue
5. Experimentation showed that IL-1β, a cytokine produced by immune cells, directly induced airway epithelial progenitor cells to differentiate into mature lung lining cells. They do this by decreasing SOX9 expression and proliferation, driving lung epithelial progenitor cells to stop self-renewal.

Publication:
J.L. Barnes et al. (2023) ‘Early human lung immune cell development and its role in epithelial cell fate.' Science Immunology. DOI: 10.1126/sciimmunol.adf9988

Funding:
This research was supported by Wellcome. For full funding acknowledgements, please refer to the publication.

Selected websites:

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About Wellcome
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