Early pregnancy depends on a remarkable act of coordination. Before the placenta can nourish a developing fetus, the fetus must “land” safely and connect to the mother’s blood supply—a process guided by a specialized group of immune cells called uterine natural killer cells, or uNK cells.
A new peer-reviewed study from the University of Alabama at Birmingham, supported by the National Institutes of Health and published today in Science Translational Medicinehas revealed a critical role in successful pregnancies for an immune switch called NFAT that helps uNK cells settle in the uterus and perform this critical guidance task. When the switch is down, fewer natural killer cells are directed to the uterus—and pregnancy complications can follow.
This discovery opens a whole new window into how the immune system supports healthy pregnancy. Seeing NFAT acting as an on-off switch in uterine NK cells was a surprise and gives us a definite lead as to why some pregnancies are headed for complications. This opens up a whole new world of research.”
Paige Porrett, MD, Ph.D., lead study author and professor of surgery and obstetrics and gynecology, Vera Hauptfeld-Dolejsek Endowed Professor of Transplant Immunology at UAB Heersink School of Medicine
Because this matters
The findings offer new insight into the biology behind preeclampsia, implantation failure, inadequate blood flow to the placenta and some early pregnancy losses—conditions that affect many pregnant patients, not just those who have undergone organ transplants.
The team’s expertise in uterine transplantation provided a unique opportunity to study the immune environment in pregnancy. But the mechanism they uncovered appears to be a fundamental part of human placental development.
“This is not just a transplant story,” Porett said. “We used transplantation as a lens, but biology can be mapped to normal and high-risk pregnancies. The benefits of this work are potentially for all pregnant patients.”
What did the researchers find?
The UAB scientists discovered that NFAT controls whether uNK cells become “tissue-permanent,” a necessary step that allows them to remain in the uterine lining and remodel maternal blood vessels for early placental development.
Until now, NFAT was known for its role in T cells, but had never been described in the context of uterine or pregnancy NK cells.
“This is a new pathway for immune cells to acquire that we didn’t know about before,” Porrett said. “Now we’re showing humans that biology we’ve only ever seen in mice applies. As a result, this opens up a whole new world of research.”
Technology has made the invisible visible
The team used single-cell RNA sequencing, a powerful modern tool that measures the activity of each gene in individual cells. This level of detail allowed researchers to see gene programs shift across thousands of cells—something older approaches couldn’t capture, especially in tissues as dynamic as the uterus.
“Sequencing a cell allows us to see, cell by cell, the gene programs that were changing,” Porett said. “You need that sensitivity to identify a path like this.”
Review of drugs commonly used in pregnancy
The study also raises important scientific questions about tacrolimus, a standard immunosuppressive drug taken by nearly all solid organ transplant recipients.
While tacrolimus is highly effective at preventing rejection—and previous studies have long shown that it does not increase the risk of birth defects—the new findings suggest that reducing NFAT signaling with the use of this drug may increase the risk of placental complications.
“Tacrolimus works incredibly well, but now we’ve identified a biological reason to rethink how it’s used in pregnancy,” Porrett said. “We have to do the hard work of finding safer alternatives for pregnant patients while preventing rejection.”
The researchers stress that no changes in medication should be made based on this study alone. Instead, the findings provide a mechanistic basis for the next phase of research: identifying alternative drugs or timing strategies that protect both the pregnancy and the transplanted organ.
“It’s a balance,” Porett said. “Tacrolimus is a workhorse and any change should be evidence-based.”
What’s next
Beyond transplant recipients, the researchers say the work opens new avenues for understanding pregnancy complications in patients who are not immunocompromised. The team plans to map how immunosuppressive drugs affect other immune and non-immune cell types in the uterus — including stromal and epithelial cells — to understand the broader biological landscape.
“This human data is powerful, but it’s largely associative,” Porett said. “We need to validate causality and understand how other types of uterine cells react. That’s the hard work ahead of us—and it’s how we turn a discovery into better outcomes.”
Porrett’s co-authors on the study, “NFAT inhibition after human uterine transplantation promotes tissue NK cell loss and associated pregnancy complications,” include UAB’s Rebecca Asiimwe, Brittney Knott, Morgan E. Greene, Emma D. Wright, Markayla Bell, Danielni D. Procópio, Stephanie Clevenger, Jayme E. Locke, Brian E. Brocato, Constantine M. Burgan, Richard Burney, Nitin Arora, Virginia E. Duncan, Holly E. Richter, Deidre Gunn, and Shawn C. Little; Michael V. Gonzalez, University of Pennsylvania; and Aharon G. Freud, The Ohio State University.
Support came from National Institutes of Health grants R01AI177369, R01AI145905, and R01CA208353. UAB Center for Women’s Reproductive Health. UAB AMC21 grants. seed funding from UAB Heersink School of Medicine. and American Cancer Society Investigator Grants #RSG-23-1153857-01-IBCD, F31HD114429 and T32GM135028.
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