OBJECTIVE: To describe the role of T-regulatory lymphocytes in pathogenesis of preterm delivery. SETTING: Department of Obstetrics and Gynecology, General University Hospital and 1st Medical Faculty, Charles University, Prague. METHOD: T-regulatory lymphocytes modulate the immune system, secure the tolerance to own antigens and prevent autoimmune disease. During pregnancy is maternal immunity in contact with the semi-allogeneic fetus due to the fetomaternal crosstalk. It seems that maternal immunity and T-regulatory lymphocytes have an effect on premature birth and other pregnancy pathologies. According to the latest data, their role in the immunomodulation of pregnant women seems to be very significant, although we still do not understand many mechanisms.
- Keywords
- T-regulatory cells, premature birth immunomodulation in pregancy.,
- MeSH
- Immunomodulation MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Fetus immunology MeSH
- Premature Birth physiopathology MeSH
- T-Lymphocytes, Regulatory immunology metabolism MeSH
- Pregnancy MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Accumulating evidence suggests that spontaneous preterm labor is a syndrome caused by multiple pathological processes. The breakdown of maternal-fetal tolerance has been proposed as a key mechanism of idiopathic spontaneous preterm labor, often viewed as a chronic inflammatory process resulting from the maternal immune system's impaired tolerance of the fetus from early pregnancy. Regulatory T cells are crucial for maintaining maternal-fetal tolerance. Even a partial reduction in their levels can disrupt this tolerance, leading to adverse pregnancy outcomes such as preterm labor. Given the complexity of the T lymphocyte-mediated immune response, identifying candidate signaling pathways involved in maternal-fetal tolerance is challenging. However, current literature highlights the importance of the functional and developmental markers FoxP3, CD45RA, Helios, and CD39 due to their immunosuppressive abilities essential for maintaining pregnancy. OBJECTIVE: This study aimed to determine whether changes in numbers of selected regulatory T cell subpopulations in the first trimester are associated with subsequent spontaneous preterm labor. STUDY DESIGN: This prospective study enrolled 43 women with early singleton pregnancies, excluding those with autoimmune diseases, diabetes mellitus (type 1, type 2), primary hypertension, or who had been treated with vaginal progesterone prior to sample collection. We analyzed regulatory T cell subpopulations in maternal circulation using the DURAClone IM T cell kit, focusing on the following subsets: CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-. RESULTS: Among the participants, 7 experienced spontaneous preterm labor between the 23rd and 33rd weeks of gestation, while 36 delivered at term. The preterm group showed a significant reduction in numbers of all analyzed regulatory T cell subpopulations: CD4+CD25+FoxP3+ (median 0.0410×10ˆ9/L vs median 0.0550×10ˆ9/L, P=.0217), CD4+CD25+FoxP3+CD45RA- (median 0.0310×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0216), CD4+CD25+FoxP3+Helios+ (median 0.0270×10ˆ9/L vs median 0.0370×10ˆ9/L, P=.0260), CD4+CD25+FoxP3+CD39- (median 0.0300×10ˆ9/L vs median 0.0420×10ˆ9/L, P=.0427). CONCLUSION: Early first trimester alterations in specific regulatory T cell subpopulations, including diminished levels of CD4+CD25+FoxP3+, CD4+CD25+FoxP3+CD45RA-, CD4+CD25+FoxP3+Helios+, and CD4+CD25+FoxP3+CD39-, are associated with idiopathic spontaneous preterm labor. These findings suggest that early changes in these lymphocyte subpopulations may be linked to spontaneous preterm birth. This highlights the need for further research to understand the mechanisms underlying regulatory T-cell dynamics and their impact on pregnancy outcomes.
- Keywords
- CD25, CD39, CD4, CD45, FoxP3, Helios, anti-fetal rejection, early pregnancy, immunology, immunosuppression, maternal-fetal tolerance, preterm labor, regulatory T cells,
- MeSH
- Leukocyte Common Antigens metabolism MeSH
- Apyrase immunology MeSH
- Antigens, CD immunology MeSH
- Adult MeSH
- Forkhead Transcription Factors * metabolism MeSH
- Humans MeSH
- Young Adult MeSH
- Obstetric Labor, Premature * immunology MeSH
- Prospective Studies MeSH
- Pregnancy Trimester, First immunology MeSH
- T-Lymphocytes, Regulatory * immunology MeSH
- Pregnancy MeSH
- Ikaros Transcription Factor MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Young Adult MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Leukocyte Common Antigens MeSH
- Apyrase MeSH
- Antigens, CD MeSH
- CD39 antigen MeSH Browser
- Forkhead Transcription Factors * MeSH
- FOXP3 protein, human MeSH Browser
- IKZF2 protein, human MeSH Browser
- Ikaros Transcription Factor MeSH
Recent discoveries suggest that T-regulatory lymphocytes (Treg) might play an important role in the pathophysiology of preterm labor. The aim of this study was to assess the relationship among the levels of maternal circulating Treg cells, uterine cervical length, and the risk of preterm labor. Sixty women with regular contractions and/or cervical incompetence at 24-32 weeks' gestation were recruited into a prospective study. Each patient underwent transvaginal ultrasound examination of the cervical length, and regulatory T cells were quantified in peripheral blood samples by flow cytometry. Patients with cervical incompetence were prescribed vaginal progesterone until birth. Measurements of Treg levels and cervical length correlated with the timing of labor. The risk of preterm labor happening within 48 h of testing was demonstrated to be almost 35 times higher (OR=35.21, CI 13.3; 214, p<0.001) in the group with simultaneously low Treg values (<0.031 × 10(9)/L) and a shortened uterine cervix (<17.5mm), compared with the situation where both of these values were normal. Similar results were found in predicting preterm delivery before 34 weeks, or between 34 and 37 weeks. A statistically nonsignificant trend toward increased cervical length and increased Treg count was noted in the women on progesterone treatment. We show for the first time that the combined assessment of Treg cell count and cervical length is a much better predictor of preterm delivery than either parameter used on its own. This combined approach may offer clinical application in patients who present with risk factors for preterm labor.
- Keywords
- Cervical incompetence, Preterm labor, T-regulatory lymphocytes, Ultrasound cervical length,
- MeSH
- Cervix Uteri cytology physiology MeSH
- Adult MeSH
- Humans MeSH
- Cervical Length Measurement * MeSH
- Infant, Newborn MeSH
- CD4 Lymphocyte Count * MeSH
- Obstetric Labor, Premature epidemiology immunology physiopathology MeSH
- Progesterone administration & dosage therapeutic use MeSH
- Prospective Studies MeSH
- T-Lymphocytes, Regulatory immunology MeSH
- Risk MeSH
- Pregnancy MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Progesterone MeSH
Regulatory T cells (Tregs) play a critical role in the maintenance of a pregnancy. While the kinetics of the number of peripheral blood Tregs has been satisfactorily described in mouse models, analysis of these cell populations in human pregnancy is complicated by high variability in the quantity of Tregs and inconsistencies in the markers used for detecting different types of Treg. In the light of this, we set out to investigate the kinetics of various types of Treg, including CD45RA, GARP and PD-1(+) Tregs, in the peripheral blood of pregnant women in the first, second and third trimester, and at the time of delivery. Tregs, defined as a CD4(+)CD25(++)CD127(dim)Foxp3(+) population of leucocytes, were detected using flow cytometry. Natural thymus-derived Tregs and induced Tregs in the peripheral blood were distinguished by the expression or absence of a Helios marker, respectively. Our results showed that during normal pregnancy the sizes of various Treg subpopulations varied across women and also in an individual woman did not remain constant but varied significantly, most notable being the decrease observed at the time of delivery. Helios(-) cells were significantly less frequent in the peripheral blood of healthy pregnant women than Helios(+) cells, and the majority of Tregs were Helios(+)PD-1(+) Tregs.
- Keywords
- CD45RA, GARP, Helios, PD-1, Treg, normal pregnancy,
- MeSH
- Cell Differentiation MeSH
- Forkhead Transcription Factors metabolism MeSH
- Immunophenotyping MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Lymphocyte Count MeSH
- Flow Cytometry MeSH
- T-Lymphocytes, Regulatory immunology MeSH
- T-Lymphocyte Subsets immunology MeSH
- Pregnancy immunology MeSH
- Thymus Gland immunology MeSH
- Transforming Growth Factor beta blood MeSH
- Ikaros Transcription Factor metabolism MeSH
- Healthy Volunteers MeSH
- Check Tag
- Humans MeSH
- Pregnancy immunology MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Forkhead Transcription Factors MeSH
- FOXP3 protein, human MeSH Browser
- IKZF2 protein, human MeSH Browser
- Transforming Growth Factor beta MeSH
- Ikaros Transcription Factor MeSH
Allergy is one of the most common diseases with constantly increasing incidence. The identification of prognostic markers pointing to increased risk of allergy development is of importance. Cord blood represents a suitable source of cells for searching for such prognostic markers. In our previous work, we described the increased reactivity of cord blood cells of newborns of allergic mothers in comparison to newborns of healthy mothers, which raised the question of whether or not this was due to the impaired function of regulatory T cells (T(regs)) in high-risk children. Therefore, the proportion and functional properties of T(regs) in cord blood of children of healthy and allergic mothers were estimated by flow cytometry. The proportion of T(regs) [CD4(+)CD25(high)CD127(low) forkhead box protein 3 (FoxP3(+))] in cord blood of children of allergic mothers tends to be higher while, in contrast, the median of fluorescence intensity of FoxP3 was increased significantly in the healthy group. Intracellular presence of regulatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-beta was also higher in T(regs) of children of healthy mothers. Although we detected an increased proportion of T(regs) in cord blood of children of allergic mothers, the functional indicators (intracellular presence of regulatory cytokines IL-10 and TGF-beta, median of fluorescence intensity of FoxP3) of those T(regs) were lower in comparison to the healthy group. We can conclude that impaired function of T(regs) in cord blood of children of allergic mothers could be compensated partially by their increased number. Insufficient function of T(regs) could facilitate allergen sensitization in high-risk individuals after subsequent allergen encounter.
- MeSH
- Hypersensitivity blood immunology MeSH
- CD4 Antigens metabolism MeSH
- Fetal Blood cytology immunology metabolism MeSH
- Forkhead Transcription Factors immunology metabolism MeSH
- Interleukin-10 blood metabolism MeSH
- Humans MeSH
- Infant, Newborn MeSH
- Flow Cytometry MeSH
- Interleukin-2 Receptor alpha Subunit metabolism MeSH
- Interleukin-7 Receptor alpha Subunit metabolism MeSH
- T-Lymphocytes, Regulatory immunology metabolism MeSH
- Case-Control Studies MeSH
- Pregnancy MeSH
- Transforming Growth Factor beta blood metabolism MeSH
- Check Tag
- Humans MeSH
- Infant, Newborn MeSH
- Pregnancy MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CD4 Antigens MeSH
- Forkhead Transcription Factors MeSH
- FOXP3 protein, human MeSH Browser
- IL2RA protein, human MeSH Browser
- Interleukin-10 MeSH
- Interleukin-2 Receptor alpha Subunit MeSH
- Interleukin-7 Receptor alpha Subunit MeSH
- Transforming Growth Factor beta MeSH
