Cellular crosstalk between mother and offspring is more complex than expected

Scientists have known for a long time that pregnancy requires a mother’s body to regulate in order that her immune system doesn’t attack the growing fetus as if it were a hostile foreign invader. Yet despite learning an incredible deal more in regards to the immunology of pregnancy in recent times, a brand new study shows that the cellular crosstalk between a mother and her offspring is much more complex and long-lasting than expected.

The study was published online Sept. 21, 2023, within the journal Science by a research team led by Sing Sing Way, MD, PhD, Division of Infectious Diseases at Cincinnati Kid’s and the Center for Inflammation and Tolerance.

By investigating how prior pregnancy changes the outcomes of future pregnancies–or in other words how moms remember their babies–our findings add a brand new dimension to our understanding of how pregnancy works. Nature has designed built-in resiliency in moms that generally reduces the chance of preterm birth, preeclampsia, and stillbirth in women who’ve a previous healthy pregnancy. If we are able to learn ways to mimic these strategies, we could also be higher capable of prevent complications in high-risk pregnancies.”

Sing Sing Way, MD, PhD, Division of Infectious Diseases at Cincinnati Kid’s

Along with potentially making progress against the leading reason for infant mortality, Way says understanding how the immune system changes while pregnant could influence other research fields including vaccine development, autoimmunity research, and the best way to prevent organ transplant rejection.

How mothers remember their babies

In 2012, Way and colleagues published a study in Nature that exposed how the experience of a primary pregnancy makes a girl’s body much less more likely to reject a second pregnancy with the identical father.

Along with previously known short-term immune system adjustments, the researchers found that the mother’s body keeps a longer-term supply of immune suppressive T cells that specifically recognize the following fetus by the identical couple. These suppressive T cells instruct the remainder of the immune system to face down because the pregnancy develops and linger within the mother’s body for years after giving birth.

For immunity against infection, such “memory” cells often require a relentless, low level of exposure to the invading pathogen. So, initially, scientists were surprised to seek out these suppressive cells persisting in moms well beyond childbirth.

The brand new study in Science reports that maintaining protective memory suppressive T cells is mediated by tiny populations of baby cells that remain in moms after pregnancy called fetal microchimeric cells. This finding provides further biological evidence to support a well known special connection between moms and their children.

“Very small numbers of fetal cells will be present in the center, liver, intestine, uterus and other tissues,” Way says. “The proven fact that we’re made up of greater than just cells with our own genetics, but in addition cells from our moms and our kids is a captivating idea.”

This influence linked to fetal cells builds on research Way and colleagues published in Cell in 2015 that shows children maintain a small supply of cells transferred from their moms while pregnant called maternal microchimeric cells. Even a few years later, these cells help explain why an organ transplant from an individual’s mother is more likely to achieve success in comparison with a donor organ from their father.

But there’s more to the story, Way says.

This potentially wide assortment of genetically foreign cells in women, including maternal microchimeric cells from their mother and unique fetal microchimeric cells from each pregnancy raises fundamental recent questions on how microchimeric cells interact with one another, and the boundaries of their accumulation. The present Science paper shows that every individual can have just one set of microchimeric cells at a time.

Fetal microchimeric cells remaining in moms from a primary pregnancy get displaced by recent fetal cells when moms turn into pregnant again. Meanwhile, once a grown daughter becomes pregnant, fetal microchimeric cells displace maternal microchimeric cells causing her to immunologically “forget” her mother.

“This transience for individual sets of microchimeric cells is remarkable, especially considering their protective advantages on pregnancy outcomes, they usually represent just one in one million cells,” Way says.

Nevertheless, the brand new research also shows that moms never fully forget their children in the identical way daughters forget their moms. While the provision of protective fetal microchimeric cells reflect only essentially the most recent pregnancy, a small variety of suppressive T cells from each pregnancy lives on in a latent form throughout the mother. They’ll linger for years, until called into motion by a brand new pregnancy.

“This was an unexpected finding,” Way says. “These memory immune cells with latent suppressive properties act as a fail-safe mechanism along with the protection from traditional memory suppressive T cells.”

Implications for high-risk pregnancy

While the brand new study is predicated on studying mouse models, the co-authors say a body of research already exists demonstrating the cellular crosstalk observed within the mice also happens in humans.

One emerging theory that requires further study is that a girl’s immune system might also “remember” bad pregnancy outcomes in much the identical way it remembers good outcomes.

“The challenge will likely be to discover specifically what a mother’s immune system retains from a pregnancy with a poor final result,” Way says. “If we are able to isolate how those mechanisms differ from a healthy final result then we might have a goal for developing improved treatments to enhance outcomes in high-risk pregnancies.”

Way says it would likely take several years to translate the brand new study’s findings into possible treatments that could possibly be tested in clinical trials.

Implications for vaccine research

While really useful for years by some experts, awareness has grown in recent times that providing vaccines to pregnant woman can protect their newborns from infectious disease threats long before the babies can directly receive their very own vaccines.

In June 2022, Way and colleagues detailed in Nature how moms can produce “super antibodies” that may protect newborns from infectious threats more effectively than previously thought possible. Their findings add weight to recommendations that pregnant women receive all of the vaccines available to them.

Just in August, that list of vaccines grew when the US Food and Drug Administration approved the primary vaccine that will be given to pregnant women to guard newborns from RSV–the No. 1 reason for lower respiratory tract illness in infants and toddlers. Around the globe, some 45,000 children die every year from RSV, including about 300 children a 12 months in the US. One other 80,000 babies a 12 months within the U.S. get so sick from RSV that they require hospital care.

With recent understanding emerging about how the immune system functions while pregnant, Way predicts that much more vaccines will come along to guard each mother and child.

“We are only starting to grasp how moms immunologically tolerate their babies while pregnant. Considering parity or the outcomes of prior pregnancy on the outcomes of future pregnancies add an exciting recent dimension for investigating how pregnancy works,” Way says. “However, given the importance of reproductive fitness in trait selection, immunology learned from moms and babies can open up recent ways to enhance vaccines, autoimmunity and transplantation.”

About this study

Along with Way, co-authors from Cincinnati Kid’s included co-first authors Tzu-Yu Shao, PhD, and Jeremy Kinder, PhD; and contributors Gavin Harper, BS, Giang Pham, PhD, Yanyan Peng, PhD, Bryan Sherman, BS, Yuehong Wu, BS, Alexandra Iten, BS, Yueh-Chiang Hu, PhD, Abigail Russi, MD, PhD, John Erickson, MD, PhD, and Hilary Miller-Handley, MD. Co-authors also included University of Cincinnati researchers James Liu, MD, and Emily Gregory, MD.

Funding sources for this study include the National Institutes of Health (DP1AI131080, R01AI120202, R01AI124657); the HHMI Faculty Scholar’s Program; the Burroughs Wellcome Fund; and the March of Dimes Ohio Collaborative.