Cited by 374IL-33, ST2, and ILC PathwaysT-cell and B-cell ImmunologyBirth, Development, and Health

Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

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van de Pavert, Serge A., Ferreira, Manuela, Domingues, Rita G., Ribeiro, Hélder, Molenaar, Rosalie, Moreira-Santos, Lara, Almeida, Francisca F., Ibiza, Sales +17 more·2014·Nature

Abstract

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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  • Recent studies have highlighted the critical role of RA in the derivation of embryonic hematopoietic cells, lymphoid organs, and Langerhans cells that reside specifically in the epidermis.

    “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.”
  • Levels of retinoids obtained from the maternal diet increase the size of secondary lymphoid organs and the efficacy of adult immune responses.

    “the levels of retinoids obtained from the maternal diet increase the size of secondary lymphoid organs and the efficacy of adult immune responses13”

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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)
Venue
Nature
Published
2014-03-19
Volume
508
Issue
7494
Pages
123-127
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
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
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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