Microbial exposure during early human development primes fetal immune cells

A N Mishra ,Florent Ginhoux,Ravid Straussman,Svetoslav Chakarov,Ankur Sharma,David Vermijlen,Ghee Chuan Lai,Nurhidaya Binte Shadan,Costerwell Khyriem,Charles Antoine Dutertre,Jerry Kok Yen Chan,Fabien Cottier,Rhea Pai,Edwin Shepherdson,Shabnam Khalilnezhad,Gillian Low,Adhika Shanti,Gurmit Singh Naranjan Singh,Pei Xiang Hor,Aviva Rotter-Maskowitz,Salvatore Albani,Thet Tun Aung,Naomi Mcgovern,Andrea Lee,Noam Shental,Norman Pavelka,Avery Khoo May Lee,Alrina Shin Min Tan,Garold Fuks,Mahesh Choolani,Phyllis Chen,Yiping Fan,Jing Yao Leong ,Kandhadayar G Srinivasan ,Benoît Malleret ,Richard L Wong ,Xiao Meng Zhang

doi:10.1016/j.cell.2021.04.039

Abstract

SummaryThe human fetal immune system begins to develop early during gestation; however, factors responsible for fetal immune-priming remain elusive. We explored potential exposure to microbial agents in utero and their contribution toward activation of memory T cells in fetal tissues. We profiled microbes across fetal organs using 16S rRNA gene sequencing and detected low but consistent microbial signal in fetal gut, skin, placenta, and lungs in the 2nd trimester of gestation. We identified several live bacterial strains including Staphylococcus and Lactobacillus in fetal tissues, which induced in vitro activation of memory T cells in fetal mesenteric lymph node, supporting the role of microbial exposure in fetal immune-priming. Finally, using SEM and RNA-ISH, we visualized discrete localization of bacteria-like structures and eubacterial-RNA within 14th weeks fetal gut lumen. These findings indicate selective presence of live microbes in fetal organs during the 2nd trimester of gestation and have broader implications toward the establishment of immune competency and priming before birth.

Highlights

The human fetal immune system is known to develop early during gestation with significant diversity in its immune repertoire and apparent sensitivity toward external antigens
T cell pool during the 2nd trimester of human fetal development is diverse and competent To study the fetal immune system and its microbial components, we established a careful protocol for collection and processing of fetal tissues (McGovern et al, 2017)
The study is divided into four stages: T cell profiling by mass cytometry (CyTOF), 16S rRNA gene sequencing for bacterial identification, culture-based sequencing of live fetal bacteria, and in vitro T cell proliferation assay to demonstrate microbial immune recognition (Figure S1A)

Summary

Introduction

The human fetal immune system is known to develop early during gestation with significant diversity in its immune repertoire and apparent sensitivity toward external antigens

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Discussion

Conclusion