The finding could lead to a better understanding of how newborns respond to both infections and vaccines, and may explain such conundrums as why many infants of HIV-positive mothers are not infected with the disease before birth, the researchers said.
It also could help scientists better understand how childhood allergies develop, as well as how to manage adult organ transplants, the researchers said. The findings are described in the Dec. 17 issue of Science and at www.sciencemag.org/content/330/6011/1695.full.html.
Until now, the fetal and infant immune system had been thought to be simply an immature form of the adult system, one that responds differently because of a lack of exposure to immune threats from the environment. The new research has unveiled an entirely different immune system in the fetus at mid-term that is derived from a completely different set of stem cells than the adult system.
“In the fetus, we found that there is an immune system whose job it is to teach the fetus to be tolerant of everything it sees, including its mother and its own organs,” said Joseph M. McCune, MD, PhD, a professor in the UCSF Division of Experimental Medicine who is a co-senior author on the paper. “After birth, a new immune system arises from a different stem cell that instead has the job of fighting everything foreign.”
The team previously had discovered that fetal immune systems are highly tolerant of cells foreign to their own bodies and hypothesized that this prevented fetuses from rejecting their mothers’ cells during pregnancy and from rejecting their own organs as they develop.
The adult immune system, by contrast, is programmed to attack anything it considers “other,” which allows the body to fight off infection, but also causes it to reject transplanted organs.
“The adult immune system’s typical role is to see something foreign and to respond by attacking and getting rid of it. The fetal system was thought in the past to fail to ‘see’ those threats, because it didn’t respond to them,” said Jeff E. Mold, first author on the paper and a postdoctoral fellow in the McCune laboratory. “What we found is that these fetal immune cells are highly prone to ‘seeing’ something foreign, but instead of attacking it, they allow the fetus to tolerate it.”
The previous studies attributed this tolerance at least in part to the extremely high percentage of “regulatory T cells”– those cells that provoke a tolerant response – in the fetal immune system. At mid-term, fetuses have roughly three times the frequency of regulatory T cells as newborns or adults, the research found.
The team set out to assess whether fetal immune cells were more likely to become regulatory T cells. They purified so-called naïve T cells – new cells never exposed to environmental assault – from mid-term fetuses and adults, and then exposed them to foreign cells. In a normal adult immune system, that would provoke an immune attack response.
They found that 70 percent of the fetal cells were activated by that exposure, compared to only 10 percent of the adult cells, refuting the notion that fetal cells don’t recognize outsiders. But of those cells that responded, twice as many of the fetal cells turned into regulatory T cells, showing that these cells are both more sensitive to stimulation and more likely to respond with tolerance, Mold said.
Researchers then sorted the cells by gene expression, expecting to see similar expression of genes in the two cell groups. In fact, they were vastly different, with thousands of genes diverging from the two cell lines. When they used blood-producing stem cells to generate new cell lines from the two groups, the same divergence occurred.
“We realized they there are in fact two blood-producing stem cells, one in the fetus that gives rise to T cells that are tolerant and another in the adult that produces T cells that attack,” Mold said.
Why that occurs, and why the immune system appears to switch over to the adult version sometime in the third trimester, remains unknown, McCune said. Further studies will attempt to determine precisely when that occurs and why, as well as whether infants are born with a range of proportions of fetal and adult immune systems – information that could change the way we vaccinate newborns or treat them for such diseases as HIV.
Co-authors of the study include Trevor D. Burt, Jose M. Rivera, Sofiya Galkina and co-senior author Cheryl A. Stoddart, all from the UCSF Department of Medicine, Division of Experimental Medicine; Jakob Michaelsson, from the Center for Infectious Medicine, Karlinska Institutet, Stockholm, Sweden; and Shivkumar Venkatasubrahmanyam and Kenneth Weinberg, of the Center for Biomedical Informatics Research and Division of Hematology/Oncology, respectively, at Stanford University, Palo Alto, Calif. Burt also is affiliated with the UCSF Division of Neonatology in the Department of Pediatrics.
Support for this work was provided by grants from the National Institutes of Health and from the Harvey V. Berneking Living Trust. The authors report no conflicts of interest in this research. Further information can be found in the full paper at www.sciencemag.org.
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For more information, visit www.ucsf.edu.
Accompanying scientific commentary: http://www.sciencemag.org/content/330/6011/1635.full.html
Follow UCSF on Twitter at http://twitter.com/ucsf
Kristen Bole | EurekAlert!
How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH
A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology