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Abstract

During gestation the developing human fetus is exposed to a diverse range of potentially immune-stimulatory molecules including semi-allogeneic antigens from maternal cells1,2, substances from ingested amniotic fluid3,4, food antigens5, and microbes6. Yet the capacity of the fetal immune system, including antigen-presenting cells, to detect and respond to such stimuli remains unclear. In particular, dendritic cells, which are crucial for effective immunity and tolerance, remain poorly characterized in the developing fetus. Here we show that subsets of antigen-presenting cells can be identified in fetal tissues and are related to adult populations of antigen-presenting cells. Similar to adult dendritic cells, fetal dendritic cells migrate to lymph nodes and respond to toll-like receptor ligation; however, they differ markedly in their response to allogeneic antigens, strongly promoting regulatory T-cell induction and inhibiting T-cell tumour-necrosis factor-α production through arginase-2 activity. Our results reveal a previously unappreciated role of dendritic cells within the developing fetus and indicate that they mediate homeostatic immune-suppressive responses during gestation.

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Change history

  • 28 June 2017

    The name and affiliation for author D.K.H.C. were corrected.

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Primary accessions

Gene Expression Omnibus

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Acknowledgements

This work was supported by Singapore Immunology Network core funding (F.G. and E.W.N.), Biomedical Research Council (BMRC) Young Investigator Grant (N.McG.), Austrian Science Fund (P19474-B13, W1248-B30 to A.E.-B.), BMRC SPF2014/00 (S.A.), and the Singapore Ministry of Health’s National Medical Research Council (J.K.Y.C, CSIRG/1383/2014, CSA(SI)/008/2016/). We thank L. Robinson for manuscript editing.

Author information

Author notes

    • Jerry Kok Yen Chan
    •  & Florent Ginhoux

    These authors contributed equally to this work.

Affiliations

  1. Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos Building, Level 3 and 4, Singapore 138648, Singapore

    • Naomi McGovern
    • , Amanda Shin
    • , Gillian Low
    • , Donovan Low
    • , Kaibo Duan
    • , Rasha Msallam
    • , Ivy Low
    • , Nurhidaya Binte Shadan
    • , Hermi R Sumatoh
    • , Erin Soon
    • , Josephine Lum
    • , Esther Mok
    • , Sandra Hubert
    • , Peter See
    • , Baptiste Janela
    • , Andreas Schlitzer
    • , Michael Poidinger
    • , Anis Larbi
    • , Evan W Newell
    • , Jerry Kok Yen Chan
    •  & Florent Ginhoux
  2. Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    • Amanda Shin
  3. Singhealth Translational Immunology and Inflammation Centre (STIIC), 20 College Road, the Academia, Level 8 Discovery Tower, Singapore 169856, Singapore

    • Leong Jing Yao
    •  & Salvatore Albani
  4. Department of Reproductive Medicine, KK Women’s and Children’s Hospital, Singapore 229899, Singapore

    • Edwin Huang Kunxiang
    • , Yiping Fan
    •  & Jerry Kok Yen Chan
  5. KK Research Centre, KK Women’s and Children’s Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore

    • Yie Hou Lee
  6. OBGYN-Academic Clinical Program, Duke-NUS, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore

    • Yie Hou Lee
  7. Department of Obstetrics & Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, NUHS Tower Block, 1E Kent Ridge Road, Singapore 119228, Singapore

    • Mahesh Choolani
    •  & Citra Nurfarah Zaini Mattar
  8. Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore

    • Mahesh Choolani
    • , Citra Nurfarah Zaini Mattar
    • , Yiping Fan
    •  & Jerry Kok Yen Chan
  9. Department of Pathology, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore

    • Tony Kiat Hon Lim
  10. Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore 119074, Singapore

    • Dedrick Kok Hong Chan
    •  & Ker-Kan Tan
  11. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore

    • Ker-Kan Tan
    •  & John Kit Chung Tam
  12. Department of Dermatology, DIAID, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria

    • Christopher Schuster
    •  & Adelheid Elbe-Bürger
  13. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK

    • Xiao-nong Wang
    • , Venetia Bigley
    • , Matthew Collin
    •  & Muzlifah Haniffa
  14. Myeloid Cell Biology, Life and Medical Science Institute, University of Bonn, 53115 Bonn, Germany

    • Andreas Schlitzer
  15. Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, 53175 Bonn, Germany

    • Andreas Schlitzer
  16. Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 119077, Singapore

    • Jerry Kok Yen Chan

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Contributions

Conceptualization, N.McG., F.G., J.K.Y.C.; methodology, N.McG., F.G., A.S., G.L., D.L., L.J.T., R.M., I.L., N.B.S., H.R.S., E.S., J.L., E.M., S.H., P.S., B.J., C.S., A.E.-B., X.N.W., E.W.N.; clinicians for help accessing samples and for discussion, E.H.K., Y.H.L., M.C., C.N.Z.M., Y.F., T.K.H.L., D.K.H.C., K.-K.T., J.K.C.T., V.B., M.C., M.H., A.S., S.A., A.L., E.W.N.; bioinformatic analysis, N.McG., K.D., M.P., F.G.; writing, N.McG., F.G., J.K.Y.C.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jerry Kok Yen Chan or Florent Ginhoux.

Reviewer Information Nature thanks V. Soumelis, S. S. Way and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    Conserved Top Ranked genes CD14+ cells.

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    Supplementary Table 2

    Conserved Bottom Ranked genes CD14+ cells.

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    Supplementary Table 3

    Conserved Top Ranked genes cDC1 cells.

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    Supplementary Table 4

    Conserved Bottom Ranked genes cDC1 cells.

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    Supplementary Table 5

    Conserved Top Ranked genes cDC2 cells.

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    Supplementary Table 6

    Conserved Bottom Ranked genes cDC2 cells.

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    Supplementary Table 7

    Ingenuity Pathway Analysis of fetal and adult CD14+ cells conserved genes.

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    Supplementary Table 8

    Ingenuity Pathway Analysis of fetal and adult cDC1 conserved genes.

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    Supplementary Table 9

    Ingenuity Pathway Analysis of fetal and adult cDC2 conserved genes.

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    Supplementary Table 10

    Z scores for list of DEG between fetal and adult APC.

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    Supplementary Table 11

    Expression level of DEG between fetal and adult APC.

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    Supplementary Table 12

    Ingenuity Pathway Analysis of DEG between fetal and adult APC.

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    Supplementary Table 13

    Antibodies used for flow cytometry and CyTOF.

About this article

Publication history

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DOI

https://doi.org/10.1038/nature22795

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