Abstract

The impact of nutritional status during fetal life on the overall health of adults has been recognized1; 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 programmed2,3. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells2,3,4,5. 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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Acknowledgements

We thank the imaging, animal and flow cytometry facilities at IMM and UPC for technical assistance; C. Mendelsohn for providing ROSA26-RARα403 mice; N. Schmolka, J. G. van Rietschoten, R. E. van Kesteren, T. H. B. Geijtenbeek, S. Gringhuis, E. Keuning, J. Peterson-Maduro, M. G. Roukens, D. D’Astolfo, M. Vermunt, A. Rijerkerk, J. Koning, J. van der Meulen and B. Oliver for technical help; and G. Vilhais-Neto, M. C. Coles and G. Eberl for discussion. M.F., L.M.-S. and R.G.D. were supported by FCT, Portugal; H.V.-F. by EMBO (1648) and ERC (207057); D.R.L. by NIH (RO1AI080885) and HHMI; M.R.M. by Dutch MS research foundation (MS 12-797); S.A.vd.P. by NGI Breakthrough Horizon (40-41009-98-9077); and R.E.M. by a VICI (918.56.612) and ALW-TOP grant (09.048).

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Author notes

    • Serge A. van de Pavert

    Present address: Hubrecht Institute–KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584 CT Utrecht, Netherlands.

    • Serge A. van de Pavert
    • , Manuela Ferreira
    • , Reina E. Mebius
    •  & Henrique Veiga-Fernandes

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands

    • Serge A. van de Pavert
    • , Rosalie Molenaar
    • , Gera Goverse
    • , Tanja Konijn
    • , Dennis Schooneman
    • , Tom O’Toole
    • , Mark R. Mizee
    • , Yasmin Habani
    •  & Reina E. Mebius
  2. Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal

    • Manuela Ferreira
    • , Rita G. Domingues
    • , Hélder Ribeiro
    • , Lara Moreira-Santos
    • , Francisca F. Almeida
    • , Sales Ibiza
    • , Inês Barbosa
    • , Carlos Labão-Almeida
    • , Cristina Godinho-Silva
    • , J. Pedro Simas
    •  & Henrique Veiga-Fernandes
  3. Erasmus Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands

    • Esther Haak
    •  & Elaine Dzierzak
  4. Howard Hughes Medical Institute, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA

    • Fabio R. Santori
    •  & Dan R. Littman
  5. Hubrecht Institute–KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584 CT Utrecht, Netherlands

    • Stefan Schulte-Merker

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Contributions

M.F. wrote the manuscript, designed, performed and analysed the experiments in Figs 1a, b, d, e, g–i, 2a–h, 3a, b, d–i and 4a, b, d–j and Extended Data Figs 1a, d–f, 2a–d, 3a–h, 4a–d, 5a–c, 6, 7a–f, 8a–d, 9a, b and 10a–c. S.A.vd.P. wrote the manuscript, designed, performed and analysed the experiments in Figs 1c, f, 3c, g–i and 4c and Extended Data Figs 1b, c, e, 5b, c and 6. R.G.D., H.R., R.M., L.M.-S., F.F.A., S.I., I.B., G.G., C.L.-A., T.K., D.S., T.O’T., M.R.M., Y.H. and S.S-M. contributed to several experiments. C.G.-S. and J.P.S. provided murid herpesvirus-4. D.R.L. and F.R.S provided Rorgt−/− embryos. E.H. and E.D. provided Ly-6A (Sca1)-GFP mice. R.E.M. and H.V.-F. supervised the work, planned the experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Henrique Veiga-Fernandes.

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DOI

https://doi.org/10.1038/nature13158

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