The early stages of pregnancy depend on amazing regulatory activities. Before the placenta can nourish the growing fetus, the fetus must safely “land” and connect to the mother’s blood supply. This process is guided by a group of specialized immune cells called uterine natural killer cells (uNK cells).
A new peer-reviewed study from the University of Alabama at Birmingham was published today with support from the National Institutes of Health. scientific translational medicinefound that an immune switch called NFAT, which helps uNK cells settle in the uterus and carry out their critical guidance tasks, plays a key role in successful pregnancy. When switched off, fewer natural killer cells reach the uterus, which can lead to pregnancy complications.
This discovery opens a whole new door into how the immune system supports a healthy pregnancy. It is surprising that NFAT acts as a resident switch for uterine NK cells, and this provides concrete clues as to why some pregnancies tend toward complications. This opens up a whole new world of research. ”
Paige Pollett, MD, lead author of the study and professor of surgery and obstetrics and gynecology, and Vera Hauptfeld-Drejsek endowed professor of transplantation immunology at UAB Hersink School of Medicine
why is this important
The findings provide new insight into the biology behind conditions that affect many pregnant patients, including organ transplant recipients, such as preeclampsia, implantation failure, poor placental blood flow, and early pregnancy loss.
The team’s expertise in uterine transplantation provided a unique opportunity to study the immune environment during pregnancy. But the mechanism they uncovered appears to be a fundamental part of human placental development.
“This is not just a transplant story,” Poletto said. “Although we used transplantation as a lens, the biology may be mapped to normal and high-risk pregnancies. The benefits of this study are potentially for all pregnant patients.”
What researchers discovered
UAB scientists discovered that NFAT controls whether uNK cells become “tissue resident.” This is a necessary step for uNK cells to remain in the endometrium and rebuild maternal blood vessels for early growth of the placenta.
Until now, NFAT was known for its role in T cells, but had never been described in relation to uterine NK cells or pregnancy.
“This is a new pathway for immune cells to become resident, and it’s something we didn’t know about before,” Pollet said. “We have shown that biology that has previously only been seen in mice also applies to humans. As a result, this opens up a whole new world of research.”
Technology that makes the invisible visible
The research team used single-cell RNA sequencing, a powerful modern tool that measures the activity of all genes within individual cells. This level of detail allowed researchers to observe changes in genetic programs across thousands of cells that older approaches could not capture, especially in dynamic tissues like the uterus.
“Single-cell sequencing allows us to look at changing genetic programs cell by cell,” Pollett said. “You need that granularity to identify these pathways.”
Reconsidering commonly used drugs during pregnancy
The study also raises important scientific questions about tacrolimus, a standard immunosuppressive drug taken by nearly all solid organ transplant recipients.
Tacrolimus is highly effective in preventing rejection, and although previous studies have long shown that tacrolimus does not increase the risk of birth defects, new findings suggest that using this drug to reduce NFAT signals may increase the risk of placental complications.
“Tacrolimus works incredibly well, but we now know there are biological reasons to reconsider how it is used during pregnancy,” Professor Porett said. “We must do the hard work of finding alternatives that are safer for pregnant patients while preventing rejection.”
The researchers stress that medication changes should not be made based solely on this study. Rather, this finding provides a mechanistic basis for the next phase of research to identify alternative drugs and timing strategies that protect both the pregnancy and the transplanted organ.
“It’s a balance,” Pollett said. “Tacrolimus is the workhorse product and any changes must be evidence-based.”
what happens next
Researchers say this study opens new avenues for understanding pregnancy complications in non-immunocompromised patients, beyond transplant recipients. The research team plans to map how immunosuppressive drugs affect other immune and non-immune cells in the uterus, such as stromal and epithelial cells, to understand the broader biological picture.
“These human data are powerful, but mostly associative,” Pollet says. “We need to test causality and understand how other types of uterine cells respond. That’s the hard work ahead, and that’s how we can translate our findings into better outcomes.”
Pollett’s co-authors on the study, “Inhibition of NFAT after human uterus transplantation promotes tissue-resident NK cell loss and associated pregnancy complications,” include UAB’s Rebecca Asimwe, Brittney Knott, Morgan E. Green, Emma D. Wright, Markayla Bell, Daniel Epstein, Stephanie D. Yates, and Mantha Frye, Emily Boydston Procopio, Stephanie Clevenger, Jamie E. Locke, Brian E. Brocato, Constantine M. Bergan, Richard Barney, Nitin Arora, Virginia E. Duncan, Holly E. Richter, Deirdre Gunn, Sean C. Little. Michael V. Gonzalez, University of Pennsylvania; and Aharon G. Freud, Ohio State University.
Support was provided by National Institutes of Health grants R01AI177369, R01AI145905, and R01CA208353. UAB Center for Women’s Reproductive Health. UAB AMC21 grant; startup funding from UAB Heersink School of Medicine; American Cancer Society Research Scholarship #RSG-23-1153857-01-IBCD, F31HD114429 and T32GM135028.
sauce:
University of Alabama at Birmingham
Reference magazines:
Asimwe, R. others. (2026) Inhibition of NFAT after human uterus transplantation promotes tissue-resident NK cell loss and associated pregnancy complications. scientific translational medicine. DOI: 10.1126/scitranslmed.adp2196. https://www.science.org/doi/10.1126/scitranslmed.adp2196
