FETAL IMMUNOLOGICAL TOLERANCE: MECHANISMS OF FORMATION AND THE ROLE OF THE UTEROPLACENTAL BARRIER

Анотація

Fetal immunological tolerance is one of the key mechanisms underlying a successful pregnancy, ensuring the survival of the genetically semi-allogeneic fetus within the maternal organism. A central role in this process is played by the uteroplacental barrier, which not only serves as a physical interface separating the maternal and fetal circulations but also functions as an active immunoregulatory complex. Its major components include trophoblast cells, decidual tissue, regulatory T lymphocytes (Tregs), uterine natural killer (uNK) cells, placental macrophages, non-classical major histocompatibility complex molecules (HLA-G and HLA-E), cytokines, extracellular vesicles, and hormonal factors.

This review summarizes current evidence regarding the cellular and molecular mechanisms involved in the development of prenatal and postnatal fetal immunological tolerance. Dynamic changes in the immune environment throughout pregnancy are discussed, ranging from the controlled inflammatory response required for embryo implantation to the establishment of a tolerogenic microenvironment and the reactivation of pro-inflammatory signals preceding labor. Particular attention is given to the role of HLA-G in suppressing NK- and T-cell cytotoxicity, interactions between trophoblasts and decidual immune cells, the vertical transfer of maternal immune cells, fetomaternal microchimerism, and the influence of the maternal microbiota on fetal immune system programming.

Disruption of uteroplacental tolerance mechanisms is considered an important pathogenic factor in the development of preeclampsia, placental dysfunction, recurrent pregnancy loss, preterm birth, and fetal growth restriction. Current evidence on the long-term effects of intrauterine immune programming on postnatal immunity is also reviewed, including responses to infectious agents, dietary antigens, and vaccines. Available data indicate that the uteroplacental barrier represents a highly specialized immunological system that determines not only pregnancy outcomes but also the development of immune competence and long-term health of the child.

References

1. Wang, J., Han, T., & Zhu, X. (2024). Role of maternal-fetal immune tolerance in the establishment and maintenance of pregnancy. Chinese medical journal, 137(12), 1399–1406. https://doi.org/10.1097/CM9.0000000000003114

2. Menzies F. M. (2025). The Placenta as an Immunological Environment. British journal of biomedical science, 82, 14910. https://doi.org/10.3389/bjbs.2025.14910

3. Vera-Ponce, V. J., Loayza-Castro, J. A., Ballena-Caicedo, J., Valladolid-Sandoval, L. A. M., Zuzunaga-Montoya, F. E., & Gutierrez De Carrillo, C. I. (2025). Global prevalence of preeclampsia, eclampsia, and HELLP syndrome: a systematic review and meta-analysis. Frontiers in reproductive health, 7, 1706009. https://doi.org/10.3389/frph.2025.1706009

4. Balasundaram, P., & Farhana, A. (2025). Immunology at the Maternal-Fetal Interface. In StatPearls. StatPearls Publishing. https://pubmed.ncbi.nlm.nih.gov/34662056/

5. Cherayil, B. J., & Jain, N. (2024). From Womb to World: Exploring the Immunological Connections between Mother and Child. ImmunoHorizons, 8(8), 552–562. https://doi.org/10.4049/immunohorizons.2400032

6. Xu, L., Li, Y., Sang, Y., Li, D. J., & Du, M. (2021). Crosstalk Between Trophoblasts and Decidual Immune Cells: The Cornerstone of Maternal-Fetal Immunotolerance. Frontiers in immunology, 12, 642392. https://doi.org/10.3389/fimmu.2021.642392

7. Wu, S., Xie, H., Su, Y., Jia, X., Mi, Y., Jia, Y., & Ying, H. (2023). The landscape of implantation and placentation: deciphering the function of dynamic RNA methylation at the maternal-fetal interface. Frontiers in endocrinology, 14, 1205408. https://doi.org/10.3389/fendo.2023.1205408

8. Zhuang, B., Shang, J., & Yao, Y. (2021). HLA-G: An Important Mediator of Maternal-Fetal Immune-Tolerance. Frontiers in immunology, 12, 744324. https://doi.org/10.3389/fimmu.2021.744324

9. Mao, J., Feng, Y., Zhu, X., & Ma, F. (2023). The Molecular Mechanisms of HLA-G Regulatory Function on Immune Cells during Early Pregnancy. Biomolecules, 13(8), 1213. https://doi.org/10.3390/biom13081213

10. Liu, H., Huang, W., Hu, Z., Han, J., Gao, R., & Qin, L. (2026). Regulatory T cells in human pregnancy: mechanisms, dysregulation, and therapeutic perspectives. Frontiers in immunology, 17, 1815957. https://doi.org/10.3389/fimmu.2026.1815957

11. Thiele, K., Urbschat, C., Riquelme, J. I. A., Ahrendt, L. S., Wöhrle, R., Schepanski, S., Eckert, J. J., Becht, E., Qi, M., Alawi, M., Becker, M., Gagliani, N., Mittrücker, H. W., Diemert, A., & Arck, P. C. (2025). Pregnancy-acquired memory CD4+ regulatory T cells improve pregnancy outcome in mice. Nature communications, 16(1), 6522. https://doi.org/10.1038/s41467-025-61572-w

12. Thomas, J. R., Naidu, P., Appios, A., & McGovern, N. (2021). The Ontogeny and Function of Placental Macrophages. Frontiers in immunology, 12, 771054. https://doi.org/10.3389/fimmu.2021.771054

13. Stelzer, I. A., Urbschat, C., Schepanski, S., Thiele, K., Triviai, I., Wieczorek, A., Alawi, M., Ohnezeit, D., Kottlau, J., Huang, J., Fischer, N., Mittrücker, H. W., Solano, M. E., Fehse, B., Diemert, A., Stahl, F. R., & Arck, P. C. (2021). Vertically transferred maternal immune cells promote neonatal immunity against early life infections. Nature communications, 12(1), 4706. https://doi.org/10.1038/s41467-021-24719-z

14. Faas, M. M., & Smink, A. M. (2025). Shaping immunity: the influence of the maternal gut bacteria on fetal immune development. Seminars in immunopathology, 47(1), 13. https://doi.org/10.1007/s00281-025-01039-8

15. Luo, F., Liu, F., Guo, Y., Xu, W., Li, Y., Yi, J., Fournier, T., Degrelle, S., Zitouni, H., Hernandez, I., Liu, X., Huang, Y., & Yue, J. (2023). Single-cell profiling reveals immune disturbances landscape and HLA-F-mediated immune tolerance at the maternal-fetal interface in preeclampsia. Frontiers in immunology, 14, 1234577. https://doi.org/10.3389/fimmu.2023.1234577

16. World Health Organization. (2025). Preterm birth. https://www.who.int/news-room/fact-sheets/detail/preterm-birth

17. Konnikova L. (2025). Reframing the paradigm-rethinking placental and fetal immunity. Placenta, S0143-4004(25)00164-X. Advance online publication. https://doi.org/10.1016/j.placenta.2025.05.011