Recruit, retain, restrain: controlling T cell immunity at the maternal-fetal interface

The classical paradigm in immunology is that the immune system protects self from non-self. However, there are many cases where the immune system needs to tolerate non-self to avoid complications or collateral damage.

Perhaps the most dramatic example of this is during pregnancy. Half of the fetal genome comes from the paternal side and therefore encodes many proteins that could be recognized as “foreign” by the immune system. Despite this potential for immune conflict, most normal pregnancies manage to balance the need for immune protection against infection with immune tolerance of the fetus.

So, what is the immunological landscape at the maternal-fetal interface, and how is immunological homeostasis maintained? To answer this question, researchers in the McCartney Lab in the UW Department of Obstetrics and Gynecology in partnership with labs in Fred Hutch Vaccine and Infectious Disease Division (VIDD) and Human Biology embarked on an ambitious study to profile T cells—the ground troops of the immune system—at the placenta in healthy pregnancies. Their results were recently published in the Journal of Immunology.

“This project was a collaboration between the University of Washington Maternal Fetal Medicine and the Fred Hutch VIDD and demonstrates how technologies developed for cancer biology can be applied to other fields including pregnancy and placenta biology,” says corresponding author Dr. Stephen McCartney about their productive collaborative effort.

The authors began by obtaining placenta and blood samples from participants at the UW undergoing routine, uncomplicated cesarean section deliveries. They performed 28-color flow cytometry to map T cell populations at either the maternal or the fetal side of the placenta. They then followed this analysis with single-cell RNA sequencing to achieve a full picture of the T cell landscape at the placenta in late term pregnancy.

Through this work, the authors found an enrichment of memory CD8+ T cells at the maternal side of the placenta. The team identified these cells as tissue resident T cells (TRMs). Taking advantage of sex mismatches between mother and fetus, the researchers were able to conclusively demonstrate that these TRMs originate from the maternal side.

The maternal TRMs are highly activated, meaning that they have undergone priming and differentiation to become memory T cells. Many also showed markers of exhaustion like programmed death ligand 1 in addition to activation markers, suggesting chronic T cell receptor activation or dysfunction.

What is stimulating these activated TRMs? Pregnancy is immunologically complicated, and any number of non-self molecules have the potential to be the stimulatory factor. To answer this question, the authors performed flow cytometry to identify T cell receptor specificities against a panel of antigens including those originating from the fetus, endogenous retroviruses, and acute pathogens.

Using the sex difference once more to their advantage, the authors found that no activated TRMs bound Y-chromosome antigens. Some responded to viral antigens from chronic or acute infections such as Epstein-Barr or influenza A. However, T cells specific for these acute pathogens were not dramatically enriched in the placenta compared to other memory T cells circulating in the blood. This suggests that most TRMs at the maternal side of the placenta are activated by general signals such as cytokines or chemokines rather than by specific antigens.

“The primary finding of our paper was that T cells isolated from the maternal-fetal interface were able to be activated in an antigen non-specific manner, similar to bystander activation in other tissues,” Dr. McCartney confirms.

So, what signals do influence T cell phenotypes at the placenta? Using a computational model that integrates signaling and gene regulatory networks, the authors predicted that several proinflammatory chemokines like CXCL10 and cytokines like interleukins (IL) 6, 15, and 18 activated T cells in a manner to promote TRM recruitment and retention at the placenta.

In cell culture, the T cells stimulated with IL-6, IL-15, or IL-18 secreted interferon gamma, a mediator of inflammation. At the maternal-fetal interface, however, elevated levels of interferon gamma was not found, suggesting additional mechanisms in the placenta are restraining T cell activation.

While these inflammatory signals get T cells to the placenta and keep them there, the risk is T cell overactivation that could be detrimental to the mother or the fetus. Therefore, other factors are needed for T cell restraint.

One possible factor the authors identified via transcriptomics was TGF-β1, a known immunomodulator. They also collaborated with the Sullivan Lab in Human Biology to profile the metabolites present at the maternal-fetal interface. They found unusually high levels of kynurenine, a tryptophan metabolite implicated in anti-inflammatory processes.

To test whether either of these compounds were influencing T cell activation, they added TGF-β1 and/or kynurenine to the interleukin-treated cells and measured secretion of inflammatory markers. They found that both compounds—alone or in combination—drastically reduced secretion of interferon gamma.

“This suggests that combined metabolic and cytokine signals can regulate immune cell activation at the maternal fetal interface,” explains Dr. McCartney. This work “highlights the need for additional research into how immunometabolism impacts immune regulation of pregnancy and whether these pathways can potentially be targeted for therapeutics for pregnancy complications such as preeclampsia and preterm birth,” he concludes.

This work has implications outside of pregnancy as well. Bystander T cell activation is implicated in autoimmune pathology (another example of blurred lines between self vs non-self), and chronic inflammation is implicated in the pathology of aging. Treatment with metabolites or cytokines could be a potential method to restore immune homeostasis after dysregulated inflammation. The immune system is a powerful tool, but sometimes it just needs to be recruited, retained, and, most importantly, restrained.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Julie McElrath, Evan Newell, and Lucas Sullivan contributed to this study.

The spotlighted research was funded by the National Institutes of Health, the National Cancer Institute, the Andy Hill Endowment Distinguished Research CARE Fund, the Institute of Translational Sciences, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Burroughs Wellcome Fund, and the Doris Duke Foundation.

Maurice NJ, Erickson JR, DeJong CS, Mair F, Taber AK, Frutoso M, Islas LV, Vigil ALBG, Lawler RL, McElrath J, Newell E, Sullivan LB, Shree R, McCartney SA. 2025. Cytokine and metabolite networks shape T cell residency and functionality at the term human maternal-fetal interface. J Immunol. doi: 10.1093/jimmun/vkaf093