title: Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity.
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.
authors.affiliation: 1] Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands [2] Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584 CT Utrecht, Netherlands. [3].
authors.forename: Serge A
authors.initials: SA
authors.lastname: van de Pavert
authors.affiliation: 1] Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal [2].
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferreira
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Rita G
authors.initials: RG
authors.lastname: Domingues
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Hélder
authors.initials: H
authors.lastname: Ribeiro
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Molenaar
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Lara
authors.initials: L
authors.lastname: Moreira-Santos
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Francisca F
authors.initials: FF
authors.lastname: Almeida
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Sales
authors.initials: S
authors.lastname: Ibiza
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Barbosa
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Gera
authors.initials: G
authors.lastname: Goverse
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Labão-Almeida
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: Cristina
authors.initials: C
authors.lastname: Godinho-Silva
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Tanja
authors.initials: T
authors.lastname: Konijn
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Schooneman
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: O'Toole
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Mizee
authors.affiliation: Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Habani
authors.affiliation: Erasmus Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: Haak
authors.affiliation: Howard Hughes Medical Institute, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Fabio R
authors.initials: FR
authors.lastname: Santori
authors.affiliation: Howard Hughes Medical Institute, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.affiliation: Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, 3584 CT Utrecht, Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
authors.affiliation: Erasmus Stem Cell Institute, Department of Cell Biology, Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands.
authors.forename: Elaine
authors.initials: E
authors.lastname: Dzierzak
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
authors.forename: J Pedro
authors.initials: JP
authors.lastname: Simas
authors.affiliation: 1] Department of Molecular Cell Biology and Immunology, VU University Medical Center, van der Boechorststraat 7, 1081BT Amsterdam, The Netherlands [2].
authors.forename: Reina E
authors.initials: RE
authors.lastname: Mebius
authors.affiliation: 1] Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal [2].
authors.forename: Henrique
authors.initials: H
authors.lastname: Veiga-Fernandes
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D004032:Diet; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000276:immunology*; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D008221:Lymphoid Tissue / Q000166:cytology / Q000187:drug effects / Q000196:embryology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014212:Tretinoin / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018168:Receptors, Retinoic Acid; D014212:Tretinoin