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
Liu H, Huang W, Hu Z, Han J, Gao R, Qin L. Regulatory T cells in human pregnancy: mechanisms, dysregulation, and therapeutic perspectives. Frontiers in immunology. 2026;17:1815957. doi:10.3389/fimmu.2026.1815957
Liu, H., et al. "Regulatory T cells in human pregnancy: mechanisms, dysregulation, and therapeutic perspectives." Frontiers in immunology, vol. 17, 2026, pp. 1815957.
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Regulatory T cells (Tregs) play a central role in maintaining immune tolerance and supporting maternal-fetal homeostasis throughout human pregnancy. Clinical and experimental evidence demonstrates that dysregulation of peripheral and decidual Tregs manifested as quantitative deficits, impaired suppressive function or lineage instability increased the risk of various pathological pregnancies, such as recurrent implantation failure (RIF), recurrent spontaneous abortion (RSA), pre-eclampsia (PE) and preterm birth (PTB). Recently, novel therapeutic strategies targeting Tregs have emerged in oncology, transplantation, and autoimmune diseases. However, their application in pathological pregnancy remains in its infancy. This review outlines the spatiotemporal dynamics of peripheral and decidual Tregs throughout gestation, elucidating their roles in maintaining maternal-fetal homeostasis and their dysregulation in pathological pregnancies. We also critically evaluated the therapeutic strategies targeting Tregs and Tregs-associated signaling pathways, including hormonal support, traditional intravenous immunoglobulin, as well as emerging interventions such as immunometabolic reprogramming and engineered cellular therapies like chimeric antigen receptor Tregs. This review may provide insights for understanding the roles of Tregs in physiological and pathological pregnancy, as well as provide new idea in the immunotherapy of pathological pregnancy.
Yang Q et al., 2026·Life Metab·Free full text on PubMed Central
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, typically characterized by irregular menstrual cycles. Our study found that postpartum menstrual cycles were largely restored in PCOS patients following assisted reproductive technology (ART) therapy. However, this recovery in menstrual cycles was not associated with any specific ART procedures. Using a PCOS mouse model, we demonstrated that elevated progesterone levels during pregnancy were responsible for normalizing estrous cyclicity. Elevated levels of progesterone induce granulosa cell apoptosis and deplete large follicles, which potentially contribute to ovarian function suppression during pregnancy. Mechanistic studies indicated that progesterone decreased follicle-stimulating hormone receptor (FSHR) expression in a GATA binding protein 2 (GATA2)-dependent manner. Interestingly, the capacity of granulosa cells to convert androgens to estrogens significantly increased after progesterone withdrawal, as evidenced by elevated cytochrome P450 family 19 subfamily A member 1 (Cyp19a1) expression in granulosa cells when stimulated with FSH. Additionally, we found that progesterone administration reduced the thickness of the uterine endometrium in PCOS mice. Our findings suggest that sustained high levels of progesterone during pregnancy can enhance ovarian reproductive endocrine capacity and improve endometrial function, thereby facilitating the recovery of postpartum menstrual cycles.
Perinatal and childhood adverse outcomes associated with assisted reproductive technology (ART) has been reported, but it remains unknown whether the initial leukocyte telomere length (LTL), which is an indicator of age-related phenotypes in later life, is affected. Here, we estimated the LTLs of 1,137 individuals from 365 families, including 202 children conceived by ART and 205 children conceived spontaneously from two centers of the China National Birth Cohort, using whole-genome sequencing (WGS) data. One-year-old children conceived by ART had shorter LTLs than those conceived spontaneously (beta, -0.36; P = 1.29 × 10-3) after adjusting for plurality, sex and other potential confounding factors. In particular, blastocyst-stage embryo transfer was associated with shorter LTL (beta, -0.54, P = 2.69 × 10-3) in children conceived by ART. The association was validated in 586 children conceived by ART from five centers using different LTL quantification methods (that is, WGS or qPCR). Blastocyst-stage embryo transfer resulted in shorter telomere lengths in mice at postnatal day 1 (P = 2.10 × 10-4) and mice at 6 months (P = 0.042). In vitro culturing of mice embryos did not result in shorter telomere lengths in the late cleavage stage, but it did suppress telomerase activity in the early blastocyst stage. Our findings demonstrate the need to evaluate the long-term consequences of ART, particularly for aging-related phenotypes, in children conceived by ART.
Zhang Y et al., 2020·European journal of cancer (Oxford, England : 1990)
It is important to explore the association between different fertility treatments and the incidence of paediatric cancer, as this will provide crucial guidance for clinical decision-making. Previous studies have explored the relationship between fertility treatments and different types of cancer in offspring, but the results are controversial. Two authors searched PubMed, Embase, Web of Science and Cochrane databases independently to acquire qualified studies. Then, the same authors extracted data from these studies and analysed these data using RevMan 5.3. Eleven case-control studies and 16 cohort studies were included in this review and meta-analysis. The relative risk of association between in vitro fertilisation (IVF) and paediatric cancer incidence was 1.01 (95% confidence interval [CI]: 0.80-1.28) in cohort studies and 1.09 (95% CI: 0.74-1.58) in case-control studies. The relative risk of association between intracytoplasmic sperm injection (ICSI) and paediatric cancer incidence was 0.97 (95% CI: 0.80-1.17) in cohort studies. The relative risk of association between fertility drugs and paediatric cancer incidence was 1.07 (95% CI: 0.68-1.69) in cohort studies and 1.12 (95% CI: 0.90-1.41) in case-control studies. The relative risk of association between frozen embryo transfer and paediatric cancer incidence was 1.37 (95% CI: 1.04-1.81) in natural pregnancy controls and 1.28 (95% CI: 0.96-1.69) in fresh embryo transfer controls. There is no evidence that IVF, ICSI and fertility drugs are associated with an increase in paediatric cancer incidence in offspring; however, frozen embryo transfer is associated with an increase in paediatric cancer incidence in the offspring, but this finding needs further research and attention.
Ng SW et al., 2020·Int J Mol Sci·Free full text on PubMed Central
Interventions to prevent pregnancy complications have been largely unsuccessful. We suggest this is because the foundation for a healthy pregnancy is laid prior to the establishment of the pregnancy at the time of endometrial decidualization. Humans are one of only a few mammalian viviparous species in which decidualization begins during the latter half of each menstrual cycle and is therefore independent of the conceptus. Failure to adequately prepare (decidualize) the endometrium hormonally, biochemically, and immunologically in anticipation of the approaching blastocyst-including the downregulation of genes involved in the proinflammatory response and resisting tissue invasion along with the increased expression of genes that promote angiogenesis, foster immune tolerance, and facilitate tissue invasion-leads to abnormal implantation/placentation and ultimately to adverse pregnancy outcome. We hypothesize, therefore, that the primary driver of pregnancy health is the quality of the soil, not the seed.
Modzelewski J et al., 2019·Ginekol Pol·Free to read
Fetal survival and development is supported by the maternal immune system. Questions regarding those mechanisms have risen from development of transplantation medicine and observation of graft rejection. Initial theories of anatomic division, fetal immune immaturity and maternal immune system inertia were found incorrect. Rejection of fetal "semi-allograft" by maternal immune system could result in pregnancy loss. Two pregnancy losses of any etiology are considered recurrent and effort should be made to name the probable cause. Immune causes of pregnancy loss are probably multifactorial, thus difficult to research and implement findings in clinical practice. Although a full understating of pregnancy loss is not established, new therapies are being developed. This review summarizes the role of lymphocytes in pregnancy development, presents data from studies on recurrent pregnancy loss patients, evidence of new therapies and ESHRE guidelines regarding immunologic investigations.
Jin LP et al., 2011·American journal of reproductive immunology (New York, N.Y. : 1989)
PROBLEM To evaluate whether the association of the costimulatory signal regulation with T helper 1/T helper 2 (Th1/Th2) bias at maternal-fetal interface in human pregnancy loss. METHOD OF STUDY The expression of CD80 and CD86 in decidual tissues and CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in the decidual T cells was compared between normal early pregnancy and miscarriage by qPCR and Western blot. The cytokine production in decidual T cells was performed by flow cytometry. The correlation of costimulatory molecule expression with Th1/Th2 cytokines was analyzed. RESULTS The CD80 mRNA and protein expression showed no significant difference between normal pregnancy and miscarriage. An increase in the expression of CD28 and CD86 was accompanied by a decrease in the expression of CTLA-4 in miscarriage in comparison with the early pregnancy. The higher expression of interleukin (IL)-2 and interferon-γ (IFN-γ), and lower expression of IL-4 and IL-10 in the decidual T cells were present in miscarriage. A correlation analysis showed a significant positive correlation of CD86 and CD28 expression with the Th1 cytokine production (IL-2 and IFN-γ), a significant negative correlation of CTLA-4 expression with the Th1 cytokine production. CONCLUSION The upregualtion of costimulatory signals on T cells might form an abnormal immune microenvironment, a shift to Th1 responses, at maternal-fetal interface, which leads to human miscarriage.
Garmendia JV et al., 2025·International journal of molecular sciences·Free full text on PubMed Central
Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 24 weeks of gestation. It affects 3-5% of women who are attempting to conceive. RPL can stem from a variety of causes and is frequently associated with psychological distress and a diminished quality of life. By contrast, recurrent implantation failure (RIF) refers to the inability to achieve a successful pregnancy after three or more high-quality embryo transfers or at least two instances of egg donation. RIF shares several causative factors with RPL. The immunological underpinnings of these conditions involve alterations in uterine NK cells, reductions in M2 macrophages and myeloid-derived suppressor cells, an increased Th1/Th2 ratio, a decreased Treg/Th17 ratio, the presence of shared ≥3 HLA alleles between partners, and autoimmune disorders. Various therapeutic approaches have been employed to address these immunological concerns, achieving varying degrees of success, although some therapies remain contentious within the medical community. This review intends to explore the immunological factors implicated in RPL and RIF and to analyze the immunological treatments employed for these conditions, which may include steroids, intravenous immunoglobulins, calcineurin inhibitors, anti-TNF antibodies, intralipid infusions, granulocyte colony-stimulating factor, and lymphocyte immunotherapy.
PMID 42064042 42064042 DOI 10.3389/fimmu.2026.1815957 10.3389/fimmu.2026.1815957 Liu et al. 2026, Liu 2026
Cite this article
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
Liu H, Huang W, Hu Z, Han J, Gao R, Qin L. Regulatory T cells in human pregnancy: mechanisms, dysregulation, and therapeutic perspectives. Frontiers in immunology. 2026;17:1815957. doi:10.3389/fimmu.2026.1815957
Liu, H., et al. "Regulatory T cells in human pregnancy: mechanisms, dysregulation, and therapeutic perspectives." Frontiers in immunology, vol. 17, 2026, pp. 1815957.
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