Human fetal dendritic cells promote prenatal T-cell immune suppression through arginase-2

Nature. 2017 Jun 29;546(7660):662-666. doi: 10.1038/nature22795.

Naomi McGovern ¹, Amanda Shin ¹ ², Gillian Low ¹, Donovan Low ¹, Kaibo Duan ¹, Leong Jing Yao ³, Rasha Msallam ¹, Ivy Low ¹, Nurhidaya Binte Shadan ¹, Hermi R Sumatoh ¹, Erin Soon ¹, Josephine Lum ¹, Esther Mok ¹, Sandra Hubert ¹, Peter See ¹, Edwin Huang Kunxiang ⁴, Yie Hou Lee ⁵ ⁶, Baptiste Janela ¹, Mahesh Choolani ⁷ ⁸, Citra Nurfarah Zaini Mattar ⁷ ⁸, Yiping Fan ⁴ ⁸, Tony Kiat Hon Lim ⁹, Dedrick Kok Hong Chan ¹⁰, Ker-Kan Tan ¹⁰ ¹¹, John Kit Chung Tam ¹¹, Christopher Schuster ¹², Adelheid Elbe-Bürger ¹², Xiao-Nong Wang ¹³, Venetia Bigley ¹³, Matthew Collin ¹³, Muzlifah Haniffa ¹³, Andreas Schlitzer ¹ ¹⁴ ¹⁵, Michael Poidinger ¹, Salvatore Albani ³, Anis Larbi ¹, Evan W Newell ¹, Jerry Kok Yen Chan ¹ ⁴ ⁸ ¹⁶, Florent Ginhoux ¹

Affiliations

1 Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos Building, Level 3 and 4, Singapore 138648, Singapore.
2 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
3 Singhealth Translational Immunology and Inflammation Centre (STIIC), 20 College Road, the Academia, Level 8 Discovery Tower, Singapore 169856, Singapore.
4 Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore 229899, Singapore.
5 KK Research Centre, KK Women's and Children's Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore.
6 OBGYN-Academic Clinical Program, Duke-NUS, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
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.
8 Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
9 Department of Pathology, Singapore General Hospital, 20 College Road, Singapore 169856, Singapore.
10 Division of Colorectal Surgery, University Surgical Cluster, National University Health System, Singapore 119074, Singapore.
11 Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore.
12 Department of Dermatology, DIAID, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
13 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
14 Myeloid Cell Biology, Life and Medical Science Institute, University of Bonn, 53115 Bonn, Germany.
15 Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, 53175 Bonn, Germany.
16 Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore 119077, Singapore.

PMID: 28614294 DOI: 10.1038/nature22795

Abstract

During gestation the developing human fetus is exposed to a diverse range of potentially immune-stimulatory molecules including semi-allogeneic antigens from maternal cells, substances from ingested amniotic fluid, food antigens, and microbes. 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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