For decades, scientists have recognized that pregnancy necessitates a mother’s body to adapt, preventing her immune system from mistaking the developing fetus as a threat. However, recent research, led by Dr. Sing Sing Way, sheds light on the intricate and enduring nature of the cellular communication between a mother and her unborn child, surpassing previous expectations.
Published in the journal Science, this study explores how prior pregnancies influence the outcomes of subsequent ones, essentially uncovering how mothers retain memories of their offspring. These findings deepen our comprehension of the mechanics of pregnancy.
Motherhood exhibits a natural resilience, reducing risks like preterm birth, preeclampsia, and stillbirth in women with prior healthy pregnancies. Learning to replicate these mechanisms could enhance our ability to prevent complications in high-risk pregnancies.
Beyond its potential to combat infant mortality, comprehending immune system changes during pregnancy could impact various research fields, from vaccine development to autoimmune studies and strategies for averting organ transplant rejection.
How moms remember their babies
In 2012, Dr. Way and his team unveiled a groundbreaking study in Nature, exposing how a woman’s first pregnancy experience significantly reduces the likelihood of rejecting a subsequent pregnancy with the same father. Going beyond the previously known short-term immune adjustments, their research revealed a remarkable phenomenon: the mother’s body retains a long-term reservoir of immune suppressive T cells that precisely recognize the next fetus from the same couple. These T cells orchestrate an immune stand-down as the pregnancy progresses and persist within the mother’s body for years postpartum.
For typical immune memory against infections, “memory” cells often require regular exposure to the invading pathogen. Thus, the persistence of these suppressive cells in mothers long after childbirth initially surprised scientists.
The recent study in Science unravels the mystery behind the preservation of these protective memory suppressive T cells, and it involves tiny populations of lingering cells known as fetal microchimeric cells. This discovery offers further biological evidence supporting the unique bond between mothers and their children.
Fetal cells, in minute quantities, can be found in various maternal tissues like the heart, liver, intestine, uterus, and more. Way remarks, “The idea that we consist of not just our own genetic cells but also cells from both our mothers and our children is truly captivating.”
This intriguing connection linked to fetal cells builds on prior research by Way and his colleagues published in Cell in 2015, which showed that children also retain a small supply of cells passed on from their mothers during pregnancy, known as maternal microchimeric cells. Even years later, these cells shed light on why organ transplants from a mother tend to be more successful than those from a father.
However, the story goes deeper. Way points out that the diverse array of genetically foreign cells within women, encompassing maternal microchimeric cells from their mothers and unique fetal microchimeric cells from each pregnancy, raises fundamental questions about how these microchimeric cells interact and accumulate. The recent Science paper confirms that an individual can possess only one set of microchimeric cells at a time.
Fetal microchimeric cells left behind in mothers from their initial pregnancy are eventually replaced by new fetal cells when subsequent pregnancies occur. Meanwhile, when a grown daughter becomes pregnant, fetal microchimeric cells supplant maternal microchimeric cells, leading to an immunological “forgetting” of her mother.
This transient nature of individual sets of microchimeric cells is astonishing, especially given their protective role in pregnancy outcomes, even though they represent only a fraction of the total cell population, roughly one in a million.
Yet, the new research also reveals that mothers never entirely forget their children in the same way daughters might forget their mothers. While the supply of protective fetal microchimeric cells reflects only the most recent pregnancy, a small number of latent suppressive T cells from each pregnancy remains within the mother. These cells can persist for years until triggered into action by a subsequent pregnancy.
“This discovery was unexpected,” Way remarks. “These latent memory immune cells with suppressive properties serve as an additional fail-safe mechanism, complementing the protection offered by conventional memory suppressive T cells.”
Implications for high-risk pregnancy
Although the recent study primarily relies on mouse models, the co-authors emphasize that an existing body of research indicates that the observed cellular communication also occurs in humans.
A fascinating emerging theory, albeit requiring further investigation, suggests that a woman’s immune system might “remember” adverse pregnancy outcomes in a manner akin to its recollection of successful pregnancies.
Dr. Way highlights the challenge of pinpointing precisely what aspects of a problematic pregnancy are retained by the immune system. Understanding these distinctions between healthy and adverse outcomes could serve as a crucial target for the development of enhanced treatments aimed at improving high-risk pregnancies.
Dr. Way also acknowledges that translating the findings of this new study into potential treatments, which could undergo clinical trials, will likely be a multi-year endeavor.
Implications for vaccine research
For quite some time, certain experts have recommended vaccinating pregnant women to safeguard their newborns against infectious diseases long before the infants can receive their own vaccinations.
In June 2022, Dr. Way and his colleagues elucidated in Nature how mothers possess the ability to generate “super antibodies” capable of providing more robust protection to newborns against infectious threats than previously believed. These findings underscore the importance of pregnant women receiving all available vaccines deemed safe for them.
In a significant development in August 2023, the US Food and Drug Administration approved the first vaccine for administration to pregnant women, offering protection to newborns against RSV, the leading cause of lower respiratory tract illness in infants and toddlers. Globally, approximately 45,000 children succumb to RSV each year, including around 300 children in the United States. Another 80,000 infants in the US experience such severe RSV infections that they require hospitalization.
With the ever-evolving understanding of how the immune system operates during pregnancy, Dr. Way anticipates the emergence of additional vaccines designed to safeguard both the mother and the child.
“We are only scratching the surface in comprehending how mothers maintain immunological tolerance towards their babies during pregnancy. Considering factors like parity and the influence of prior pregnancies on future ones introduces an exciting dimension to our exploration of pregnancy,” Dr. Way remarks.
Furthermore, Dr. Way underscores that insights gained from studying the immunology of mothers and babies can lead to innovative approaches for enhancing vaccines, advancing research in autoimmunity, and improving transplantation procedures.