Microbes in human fetuses promote immune development

ÖOver the past decade, scientists have shown that the fetus’s immune system goes online much earlier than initially thought, but what kind of antigens train immune cells and how this affects later development remains an open question. In a study published June 1 in cell, Researchers found that human fetuses in the second trimester harbor live bacteria throughout their body that can activate fetal T cells.

“The exciting thing about this paper for me is that it provides evidence, not just that there is microbial exposure in utero. . . but that it is important for the formation of the developing fetal immune system – especially memory T cells, which are then important to prepare the newborn to deal with additional antigen exposures, microbial exposures and possible infectious pathogenic exposures, “says Indira Mysorekar, a biologist at Washington University School of Medicine who wrote a comment that will appear in cell about the new course. “It supports other recently published studies suggesting that there is in-utero exposure and that it is fetal [immune] Education begins in the womb. “

In 2017, immunologist Florent Ginhoux from A * STAR in Singapore and colleagues showed that the fetal immune system is functional in the second trimester of pregnancy. “It looks like the fetal immune system is pretty functional fast and early,” he explains. The results contradicted the long-held belief that babies receive their first major immune challenge when they are born and come in contact with the outside world, starting with the vaginal microbiome, he adds. While the work of other groups has confirmed the appearance of the fetal immune system in the second trimester, it is still not clear what antigens fetal immune cells recognize.

To answer this question, Ginhoux met again with Jerry Chan and Salvatore Albani from Duke-NUS Medical School in Singapore and Naomi McGovern, a former postdoc at A * STAR who now runs her own laboratory at the University of Cambridge in the UK , teamed up. The researchers used 16S ribosomal RNA sequencing on various fetal and placental tissues – obtained from abortions in the second trimester – to show that traces of microbes were present in the fetal intestines, lungs and skin, as well as in the placenta .

To rule out contamination as a source of bacterial DNA, the researchers sent fetal samples to employees at the Weizmann Institute in Israel, who also found evidence of bacterial DNA. The team also sequenced numerous controls: the buffers used to clean tools in the hospital and laboratory, swabs from the hands of researchers handling fetal specimens and touching every surface the fetal tissue might have touched, and all Reagents that have been used Extract and sequence DNA.

By comparing the signal from the controls with that of the fetal tissue, the team identified a genetic signature that corresponds to certain microbes present in the fetuses. “It’s a low biomass signal, but it’s unlikely to be noise,” says Ginhoux.

The team grew live bacteria from fetal tissue in culture, including some of those specific microbes that were not found in the controls. Then they prepared fetal viscera – the tissue that had the largest microbial community next to the skin – for scanning electron microscopy. The intestinal tissue was from one fetus estimated to be 10 weeks gestational age and three estimated gestational age 14 weeks. “To our surprise, we were able to find microbes in the intestines of the 14-week-old fetuses, but not the 10-week-old ones,” says Ginhoux, which suggests that the bacteria colonize the intestines after a certain point of development. The bacteria were only found in certain places in the intestinal lumen, in structures that looked like they were bound to mucin, a mucous-like substance released by epithelial cells.

A representative scanning electron microscope image of a 14 week old human fetal midgut showing the mucosal area with bacteria (red arrows)

cell, doi: 10.1016 / j.cell.2021.04.039, 2021

Eventually, the researchers showed that some of the types of bacteria they found in the fetuses can activate memory T cells isolated from fetal tissue in an in vitro system they had developed to make the T cells – Monitor activation and expansion. “The T cells that we find activated in the tissue have probably been partially developed or activated to react to the isolated microbes,” explains Ginhoux. The results suggest that microbes are one of the factors involved in early human immune development and “may be the foundation of this lifelong human health and immunity.”

“It’s very fascinating to think that you are exposed to bacteria this early,” says Donna Farber, an immunologist at Columbia University who did not participate in the study. “And then the question is, where do these bacteria come from?” She asks.

“The vertical transmission of microbial organisms from mother to child is a completely unknown mechanism,” agrees Ginhoux. “There is so much communication and exchange between mother and fetus during development.”

Another open question, Mysorekar said, is how in utero exposure to microbes affects the development of the fetal immune system. “What signals are perceived or received by the fetal immune cells that initiate their formation?” She asks. This work “opens the field and really underlines that there are many questions to be clarified”.

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