AsianScientist (Jun. 15, 2017) – Fetuses are not as defenseless as previously thought. In a study published in Nature, researchers from Singapore have found that immune cells called dendritic cells appear as early as the second trimester and are capable of mounting full-fledged immune responses against infectious agents. These findings shed light on immune-related pregnancy complications such as preterm birth and recurrent miscarriages.
From an immunological point of view, the fetus developing in a pregnant woman is a foreign object and a potential target of the mother’s immune system. However, little is known about the fetus’ own immune system and how it responds to maternal cells and other foreign objects, if at all. Since the fetus generally tolerates the mother’s cells during pregnancy, it has been assumed to have an immature or defective immune system that somehow prevents it from attacking its mother.
“What we are trying to show is that just as the mother’s immune system needs to accept the baby, the baby’s also needs to accept the mother; there is a very dynamic equilibrium between the two immune systems,” said study corresponding author Dr. Florent Ginhoux from the Singapore Immunology Network (SIgN) at the Agency for Science, Technology and Research (A*STAR).
Using tissues collected from 96 fetuses ranging from 14 to 22 weeks of gestation, Ginhoux and his colleagues identified cells that express cell surface markers typical of dendritic cells, a type of immune cell that senses foreign molecules and activates other immune cells. When these fetal dendritic cells were stimulated with molecules known to activate the immune system in adults, they produced a robust immune response including the release of cytokines and the activation of T-cells.
Despite the similarities in function and cell surface marker expression, fetal dendritic cells had a different gene expression pattern from adult cells. In particular, the researchers found that a gene called arginase-2 was highly expressed in fetal dendritic cells but not adult dendritic cells.
“Arginase-2 regulates the levels of arginine, a very important amino acid that is needed for T-cell activation,” Ginhoux explained. “You can imagine that what dendritic cells are doing in fetal development is controlling the access of T-cells to ‘fuel,’ deciding how much energy the T-cells can get by controlling the levels of arginine and thereby mitigating the level of inflammation and immune activation.”
“In addition, we found that fetal dendritic cells reduce the ability of T-cells to generate a key cytokine called TNFα,” added study co-author Associate Professor Jerry Chan, senior consultant at the Department of Reproductive Medicine at KK Women’s and Children’s Hospital, Singapore. “This is interesting because the levels of TNFα are elevated in many pregnancy related conditions like preterm birth.”
The discovery of how fetal dendritic cells suppress any unwanted immune responses against maternal cells or other antigens could lead to new immunotherapies, the researchers continued.
“We could possibly engineer dendritic cells to overexpress arginase-2 to produce a local tolerogenic environment and therefore reduce autoimmunity-associated inflammation in diseases like eczema and systemic lupus erythematosus,” Chan told Asian Scientist Magazine.
“Another application that could be of interest is transplantation,” said Ginhoux. “Reinitiating the fetal program of immune suppression could prevent the body from reacting against the transplanted organ.”
The researchers next plan to take a more systematic and holistic approach to studying fetal immunity by looking at the role of immune cells other than dendritic cells. Their goal is to build what they call a single cell atlas, a comprehensive catalog of the different cell populations present at each gestational week.
“We want to understand how all of the cells in the developing fetus work together to maintain immunosuppression,” Ginhoux said.
The article can be found at: McGovern et al. (2017) Human Fetal Dendritic Cells Promote Prenatal T-cell Immune Suppression Through Arginase-2.
Copyright: Asian Scientist Magazine; Photo: Benoit Malleret/SIgN/A*STAR.
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