Exploring the Origin and Antigenic Specificity of Maternal Regulatory T Cells in Pregnancy

Ahn, Soo Hyun; Nguyen, Sean L.; Petroff, Margaret G.

doi:10.3389/fimmu.2020.01302

Cited by 21 publications

(24 citation statements)

References 97 publications

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“…In mice, depletion of Tregs using anti-CD25 monoclonal antibodies induced implantation failure and abortion in allogenic pregnancies [ 45 ]. However, the origin of Treg cells in decidua and circulation during pregnancy is still unknown [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Human placental exosomes induce maternal systemic immune tolerance by reprogramming circulating monocytes

et al. 2022

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Background The maternal immune system needs to tolerate the semi-allogeneic fetus in pregnancy. The adaptation occurs locally at the maternal–fetal interface as well as systemically through the maternal circulation. Failure to tolerate the paternal antigens may result in pregnancy complications, such as pregnancy loss and pre-eclampsia. However, the mechanism that regulates maternal immune tolerance, especially at the systemic level, is still an enigma. Here we report that the first-trimester placenta-derived exosomes (pEXOs) contribute to maternal immune tolerance by reprogramming the circulating monocytes. Results pEXOs predominantly target monocytes and pEXO-educated monocytes exhibit an immunosuppressive phenotype as demonstrated by reduced expression of marker genes for monocyte activation, T-cell activation and antigen-process/presentation at the transcriptomic level. They also have a greater propensity towards M2 polarization when compared to the monocytes without pEXO treatment. The inclusion of pEXOs in a monocyte-T-cell coculture model significantly reduces proliferation of the T helper cells and cytotoxic T cells and elevates the expansion of regulatory T cells. By integrating the microRNAome of pEXO and the transcriptomes of pEXO-educated monocytes as well as various immune cell functional assays, we demonstrate that the pEXO-derived microRNA miR-29a-3p promotes the expression of programmed cell death ligand-1, a well-known surface receptor that suppresses the adaptive immune system, by down-regulation of phosphatase and tensin homolog in monocytes. Conclusions This is the first report to show how human pEXO directly regulates monocyte functions and its molecular mechanism during early pregnancy. The results uncover the importance of pEXO in regulating the maternal systemic immune response during early pregnancy by reprogramming circulating monocytes. The study provides the basis for understanding the regulation of maternal immune tolerance to the fetal allograft. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Human placental exosomes induce maternal systemic immune tolerance by reprogramming circulating monocytes

et al. 2022

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“…One question that has arisen from the study of Tregs concerns the contributions of thymic/natural Tregs and peripheral/induced Tregs to pregnancy success, a topic that was recently reviewed. 87 Deficiency of conserved noncoding sequence 1 (CNS1), a Foxp3 element with a prominent role in peripheral Treg generation, increased immune cell infiltration of the placenta and caused fetal loss, 46 suggesting an important role for peripheral Tregs in pregnancy maintenance. More recent studies have indicated that the generation of thymic Tregs continues during pregnancy, 88,89 although this concept is still controversial.…”

Section: Regulatory T Cellsmentioning

confidence: 99%

Cellular immune responses in the pathophysiology of preeclampsia

Miller

Motomura

Galaz

et al. 2021

Journal of Leukocyte Biology

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Preeclampsia, defined as new‐onset hypertension accompanied by proteinuria occurring at 20 weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi‐systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti‐angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal‐fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.

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“…During pregnancy this results in mid-gestational differences in heart rate and mean arteriolar pressure, thus suggesting that these cell subsets may influence systemic vascular biology in the mother both developmentally and during pregnancy ( Burke et al, 2011 ). While evidence suggests that deficiency in a certain subset of T cells with regulatory properties (Treg) is associated with preeclampsia ( Cerdeira et al, 2012 ; Przybyl et al, 2015 ) our expanding knowledge of the complexity of these T cell subsets is likely to reveal associations between this disease and several members of the CD4 family of T cells ( Ahn et al, 2020 ; Saigusa et al, 2020 ; Deer et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Deficiency in CD4 T Cells Leads to Enhanced Postpartum Internal Carotid Artery Vasoconstriction in Mice: The Role of Nitric Oxide

et al. 2021

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The risk of postpartum (PP) stroke is increased in complicated pregnancies. Deficiency in CD4 T cell subsets is associated with preeclampsia and may contribute to PP vascular disease, including internal carotid artery (ICA) stenosis and stroke. We hypothesized that CD4 T cell deficiency in pregnancy would result in ICA dysregulation, including enhanced ICA vasoconstriction. We characterized the function, mechanical behavior, and structure of ICAs from C57BL/6 (WT) and CD4 deficient (CD4KO) mice, and assessed the role of NO in the control of ICA function at pre-conception and PP. WT and CD4KO mice were housed under pathogen-free conditions, mated to same-strain males, and allowed to litter or left virgin. At 3 days or 4 weeks PP, mice were euthanized. The responses to phenylephrine (PE), high K+ and acetylcholine (ACh) were assessed in pressurized ICAs before and after NOS inhibition. Passive lumen diameters were measured at 3–140 mmHg. eNOS and iNOS expression as well as the presence of T cells were evaluated by immunohistochemistry. Constriction of WT ICAs to PE was not modified PP. In contrast, responses to PE were significantly increased in ICAs from PP as compared to virgin CD4KO mice. Constriction to high K+ was not enhanced PP. ICAs from WT and CD4KO mice were equally sensitive to ACh with a significant rightward shift of dose-response curves after L-NNA treatment. NOS inhibition enhanced PE constriction of ICAs from WT virgin and PP mice. Although a similar effect was detected in ICAs of virgin CD4KO mice, no such changes were observed in vessels from PP CD4KO mice. Passive arterial distensibility at physiological levels of pressure was not modified at PP. ICA diameters were significantly increased in PP with no change in vascular wall thickness. Comparison of eNOS expression in virgin, 3 days and 4 weeks PP revealed a reduced expression in ICA from CD4 KO vs. WT PP vessels which reached significance at 4 weeks PP. iNos expression was similar and decreased over the PP period in vessels from WT and CD4KO mice. Dysregulation of the CD4 T cell population in pregnancy may make ICA vulnerable to vasospasm due to decreased NO-dependent control of ICA constriction. This may lead to cerebral hypoperfusion and increase the risk of maternal PP stroke.

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Exploring the Origin and Antigenic Specificity of Maternal Regulatory T Cells in Pregnancy

Cited by 21 publications

References 97 publications

Human placental exosomes induce maternal systemic immune tolerance by reprogramming circulating monocytes

Human placental exosomes induce maternal systemic immune tolerance by reprogramming circulating monocytes

Cellular immune responses in the pathophysiology of preeclampsia

Deficiency in CD4 T Cells Leads to Enhanced Postpartum Internal Carotid Artery Vasoconstriction in Mice: The Role of Nitric Oxide

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