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Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity
Open accessAbstract
The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.
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“Besides the neurogenic potential of RA, recent studies have highlighted the critical role of RA in the derivation of embryonic hematopoietic cells9, lymphoid organs13, and Langerhans cells that reside specifically in the epidermis16.”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [13]
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“the levels of retinoids obtained from the maternal diet increase the size of secondary lymphoid organs and the efficacy of adult immune responses13”
From Advances and challenges in retinoid delivery systems in regenerative and therapeutic medicine (2020) · cites this paper as [13]
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Metadata
- Authors
- van de Pavert, S. A., Ferreira, M., Domingues, R. G., Ribeiro, H., Molenaar, R., Moreira-Santos, L., Almeida, F. F., Ibiza, S., Barbosa, I., Goverse, G., Labão-Almeida, C., Godinho-Silva, C., Konijn, T., Schooneman, D., O’Toole, T., Mizee, M. R., Habani, Y., Haak, E., Santori, F. R., Littman, D. R., Schulte-Merker, S., Dzierzak, E., Simas, J. P., Mebius, R. E., & Veiga-Fernandes, H.
- Affiliations
- Instituto de Medicina Molecular João Lobo Antunes (PT)
- University of Lisbon (PT)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Erasmus MC (NL)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Nature
- Published
- 2014-03-19
- Volume
- 508
- Issue
- 7494
- Pages
- 123-127
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4932833
- OpenAlex
- W2076363780
- Cited by
- 374
- References
- 42
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 15 · 2023: 25 · 2022: 26 · 2021: 21 · 2020: 33 · 2019: 34 · 2018: 48 · 2017: 24 · 2016: 39 · 2015: 47 · 2014: 30
- FWCI
- 21.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Crohn's and Colitis Foundation (313089)
- National Institute of Allergy and Infectious Diseases (R01AI080885)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Birth, Development, and Health
- Keywords
- retinoic acid, ILC3, lymphoid tissue inducer cells, fetal immune development, RORγt, retinoic acid receptor, maternal nutrition
- MeSH terms
- Animals, Cell Differentiation, Diet, Female, Fetus, Immunity, Innate, Lymphoid Tissue, Mice, Inbred C57BL, Pregnancy, Prenatal Exposure Delayed Effects, Stem Cells, Tretinoin, Signal Transduction, Receptors, Retinoic Acid, Mice
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