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

Serge A van de Pavert; Manuela Ferreira; Rita G Domingues; Hélder Ribeiro; Rosalie Molenaar; Lara Moreira-Santos; Francisca F Almeida; Sales Ibiza; Inês Barbosa; Gera Goverse; Carlos Labão-Almeida; Cristina Godinho-Silva; Tanja Konijn; Dennis Schooneman; Tom O'Toole; Mark R Mizee; Yasmin Habani; Esther Haak; Fabio R Santori; Dan R Littman; Stefan Schulte-Merker; Elaine Dzierzak; J Pedro Simas; Reina E Mebius; Henrique Veiga-Fernandes

doi:10.1038/nature13158

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

Serge A van de Pavert, Manuela Ferreira, Rita G Domingues, Hélder Ribeiro, Rosalie Molenaar, Lara Moreira-Santos, Francisca F Almeida, Sales Ibiza, Inês Barbosa, Gera Goverse, Carlos Labão-Almeida, Cristina Godinho-Silva, Tanja Konijn, Dennis Schooneman, Tom O'Toole, Mark R Mizee, Yasmin Habani, Esther Haak, Fabio R Santori, Dan R LittmanStefan Schulte-Merker, Elaine Dzierzak, J Pedro Simas, Reina E Mebius, Henrique Veiga-Fernandes

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

302 Citaten (Scopus)

Samenvatting

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.

Originele taal-2	Engels
Pagina's (van-tot)	123-7
Aantal pagina's	5
Tijdschrift	Nature
Volume	508
Nummer van het tijdschrift	7494
DOI's	https://doi.org/10.1038/nature13158
Status	Gepubliceerd - 03 apr. 2014

Toegang tot document

10.1038/nature13158

Citeer dit

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., ... Veiga-Fernandes, H. (2014). Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature, 508(7494), 123-7. https://doi.org/10.1038/nature13158

@article{8463d822def444d296971e027950a2dd,

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.",

keywords = "Animals, Cell Differentiation, Diet, Female, Fetus, Immunity, Innate, Lymphoid Tissue, Mice, Mice, Inbred C57BL, Pregnancy, Prenatal Exposure Delayed Effects, Receptors, Retinoic Acid, Signal Transduction, Stem Cells, Tretinoin",

author = "{van de Pavert}, {Serge A} and Manuela Ferreira and Domingues, {Rita G} and H{\'e}lder Ribeiro and Rosalie Molenaar and Lara Moreira-Santos and Almeida, {Francisca F} and Sales Ibiza and In{\^e}s Barbosa and Gera Goverse and Carlos Lab{\~a}o-Almeida and Cristina Godinho-Silva and Tanja Konijn and Dennis Schooneman and Tom O'Toole and Mizee, {Mark R} and Yasmin Habani and Esther Haak and Santori, {Fabio R} and Littman, {Dan R} and Stefan Schulte-Merker and Elaine Dzierzak and Simas, {J Pedro} and Mebius, {Reina E} and Henrique Veiga-Fernandes",

year = "2014",

month = apr,

day = "3",

doi = "10.1038/nature13158",

language = "English",

volume = "508",

pages = "123--7",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7494",

}

van de Pavert, SA, Ferreira, M, Domingues, RG, Ribeiro, H, Molenaar, R, Moreira-Santos, L, Almeida, FF, Ibiza, S, Barbosa, I, Goverse, G, Labão-Almeida, C, Godinho-Silva, C, Konijn, T, Schooneman, D, O'Toole, T, Mizee, MR, Habani, Y, Haak, E, Santori, FR, Littman, DR, Schulte-Merker, S, Dzierzak, E, Simas, JP, Mebius, RE & Veiga-Fernandes, H 2014, 'Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity', Nature, vol. 508, nr. 7494, blz. 123-7. https://doi.org/10.1038/nature13158

TY - JOUR

T1 - Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity

AU - van de Pavert, Serge A

AU - Ferreira, Manuela

AU - Domingues, Rita G

AU - Ribeiro, Hélder

AU - Molenaar, Rosalie

AU - Moreira-Santos, Lara

AU - Almeida, Francisca F

AU - Ibiza, Sales

AU - Barbosa, Inês

AU - Goverse, Gera

AU - Labão-Almeida, Carlos

AU - Godinho-Silva, Cristina

AU - Konijn, Tanja

AU - Schooneman, Dennis

AU - O'Toole, Tom

AU - Mizee, Mark R

AU - Habani, Yasmin

AU - Haak, Esther

AU - Santori, Fabio R

AU - Littman, Dan R

AU - Schulte-Merker, Stefan

AU - Dzierzak, Elaine

AU - Simas, J Pedro

AU - Mebius, Reina E

AU - Veiga-Fernandes, Henrique

PY - 2014/4/3

Y1 - 2014/4/3

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Differentiation

KW - Diet

KW - Female

KW - Fetus

KW - Immunity, Innate

KW - Lymphoid Tissue

KW - Mice

KW - Mice, Inbred C57BL

KW - Pregnancy

KW - Prenatal Exposure Delayed Effects

KW - Receptors, Retinoic Acid

KW - Signal Transduction

KW - Stem Cells

KW - Tretinoin

U2 - 10.1038/nature13158

DO - 10.1038/nature13158

M3 - Article

C2 - 24670648

SN - 0028-0836

VL - 508

SP - 123

EP - 127

JO - Nature

JF - Nature

IS - 7494

ER -

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

Samenvatting

Toegang tot document

Vingerafdruk

Citeer dit