The Frequency of Peripheral Blood <scp>CD</scp>4+ <scp>CD</scp>25high <scp>F</scp>ox<scp>P</scp>3+ and <scp>CD</scp>4+ <scp>CD</scp>25− <scp>F</scp>ox<scp>P</scp>3+ Regulatory <scp>T</scp> Cells in Normal Pregnancy and Pre‐Eclampsia

Toldi, Gergely; Saito, Shigeru; Saito, Tomoko; Halmos, Amrita; Veresh, Zoltán; Vásárhelyi, Barna; Rigó, János; Molvarec, Attila

doi:10.1111/j.1600-0897.2012.01145.x

Cited by 78 publications

(57 citation statements)

References 25 publications

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“…Treg cells in blood of preeclamptic as opposed to healthy pregnant women (19,24,(43)(44)(45)(46)(47)(48)(49), although some previous studies did not show a difference between these groups (32,33,44). In a more recent study, by using an updated phenotyping strategy, Steinborn et al did not find any differences with regard to the whole Treg cell population, while alterations in the preeclampsia group were found in Treg subpopulations (31), in line with our findings (see below).…”

Section: Discussionsupporting

confidence: 90%

“…In humans, Treg cells are identified as CD4 + T helper cells expressing forkhead box P3 (FOXP3) (14) and high levels of the IL-2 receptor -chain, CD25 (14,15). Early reports indicated that the circulating Treg pool was expanded in normal human pregnancy (17)(18)(19)(20). However, with increasing insights in the complexity of Treg markers in humans, subsequent studies did not report increased frequency in the circulation (21)(22)(23)(24)(25).…”

Section: Introductionmentioning

confidence: 99%

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Regulatory T‐cell Subpopulations in Severe or Early‐onset Preeclampsia

Boij

Mjösberg

Svensson‐Arvelund

et al. 2015

American J Rep Immunol

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ProblemA deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. ObjectiveUtilizing recent advances in flow cytometry phenotyping, we aimed to assess whether a deficiency of Treg subpopulations occurs in preeclampsia. Method of StudySix-color flow cytometry was used for Treg phenotyping in 18 preeclamptic women (1 early-onset, 1 severe and 16 both), 20 women with normal pregnancy and 20 non-pregnant controls.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Regulatory T‐cell Subpopulations in Severe or Early‐onset Preeclampsia

Boij

Mjösberg

Svensson‐Arvelund

et al. 2015

American J Rep Immunol

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“…Many of the pathological features that we observed in our in vivo model are compatible with those previously reported in preeclamptic pregnancies, including loss of neutrophil quiescence (22) and reduction of circulating Tregs (40). Preeclampsia is a multiorgan syndrome of pregnancy that most commonly affects first-time pregnancies in the second trimester of pregnancy (2-7%) and it is a leading cause of maternal and fetal morbidity and mortality (41).…”

Section: Activated Neutrophils From Preeclamptic Pregnancies Fail To supporting

confidence: 76%

“…During healthy pregnancy, the maternal immune system adapts to allow survival of a partially histoincompatible fetus, and failure of this adaptation contributes to poor placental invasion that predates the clinical onset of preeclampsia. Studies have suggested that impaired expansion of inducible Treg (iTreg) cells (40,51), particularly in the decidua, might represent a pathogenic defect in preeclampsia. A key feature of the niT-cell population that we describe is its ability to produce IL-17.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

Nadkarni

Sferruzzi‐Perri

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

118

117

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Although neutrophils are known to be fundamental in controlling innate immune responses, their role in regulating adaptive immunity is just starting to be appreciated. We report that human neutrophils exposed to pregnancy hormones progesterone and estriol promote the establishment of maternal tolerance through the induction of a population of CD4+ T cells displaying a GARP+CD127loFOXP3+ phenotype following antigen activation. Neutrophil-induced T (niT) cells produce IL-10, IL-17, and VEGF and promote vessel growth in vitro. Neutrophil depletion during murine pregnancy leads to abnormal development of the fetal-maternal unit and reduced empbryo development, with placental architecture displaying poor trophoblast invasion and spiral artery development in the maternal decidua, accompanied by significantly attenuated niT cell numbers in draining lymph nodes. Using CD45 congenic cells, we show that induction of niT cells and their regulatory function occurs via transfer of apoptotic neutrophil-derived proteins, including forkhead box protein 1 (FOXO1), to T cells. Unlike in women with healthy pregnancies, neutrophils from blood and placental samples of preeclamptic women fail to induce niT cells as a direct consequence of their inability to transfer FOXO1 to T cells. Finally, neutrophil-selective FOXO1 knockdown leads to defective placentation and compromised embryo development, similar to that resulting from neutrophil depletion. These data define a nonredundant function of neutrophil–T cell interactions in the regulation of vascularization at the maternal–fetal interface.

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“…Studies suggest that failure of the maternal immune tolerance mechanisms precedes the development of placental ischemia and oxidative stress, both of which are known to be involved in the pathophysiology of preeclampsia (18). Clinical studies have shown that there is a decrease in the number of T Reg s in preeclamptic women compared with women with normal pregnancies (5,38,42,43). Our data echo these findings in that the T Reg population is a low percentage among total CD4 ϩ T cells isolated from RUPP rats.…”

Section: /Cd25supporting

confidence: 32%

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

Cornelius

Amaral

Harmon

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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The reduced uterine perfusion pressure (RUPP) rat model of preeclampsia exhibits much of the pathology characterizing this disease, such as hypertension, inflammation, suppressed regulatory T cells (T Regs), reactive oxygen species (ROS), and autoantibodies to the ANG II type I receptor (AT1-AA) during pregnancy. The objective of this study was to determine whether supplementation of normal pregnant (NP) TRegs into RUPP rats would attenuate the pathophysiology associated with preeclampsia during pregnancy. CD4 ϩ /CD25ϩ T cells were isolated from spleens of NP and RUPP rats, cultured, and injected into gestation day (GD) 12 normal pregnant rats that underwent the RUPP procedure on GD 14. On GD 1, mean arterial pressure (MAP) was recorded, and blood and tissues were collected for analysis. One-way ANOVA was used for statistical analysis. MAP increased from 99 Ϯ 2 mmHg in NP (n ϭ 12) to 127 Ϯ 2 mmHg in RUPP (n ϭ 21) but decreased to 118 Ϯ 2 mmHg in RUPPϩNP TRegs (n ϭ 17). Circulating IL-6 and IL-10 were not significantly changed, while circulating TNF-␣ and IL-17 were significantly decreased after supplementation of TRegs. Placental and renal ROS were 339 Ϯ 58.7 and 603 Ϯ 88.1 RLU·min Ϫ1 ·mgϪ1 in RUPP and significantly decreased to 178 Ϯ 27.8 and 171 Ϯ 55.6 RLU·min Ϫ1 ·mg Ϫ1 , respectively, in RUPPϩNP TRegs; AT1-AA was 17.81 Ϯ 1.1 beats per minute (bpm) in RUPP but was attenuated to 0.50 Ϯ 0.3 bpm with NP TRegs. This study demonstrates that NP TRegs can significantly improve inflammatory mediators, such as IL-17, TNF-␣, and AT 1-AA, which have been shown to increase blood pressure during pregnancy.hypertension; pregnancy; inflammation; oxidative stress; regulatory T cells PREECLAMPSIA IS A PREGNANCY-ASSOCIATED disorder that affects 5-8% of pregnancies and is a major cause of maternal, fetal, and neonatal morbidity and mortality (9,29,37). Hallmark characteristics of preeclampsia are new-onset hypertension after 20 wk gestation, proteinuria, chronic immune activation, fetal growth restriction, and maternal endothelial dysfunction. The pathophysiological mechanisms that lead to the development of preeclampsia are poorly understood. It is thought that poor invasion of trophoblasts leads to insufficient spiral artery remodeling, resulting in placental ischemia (4, 10, 31). The hypoxic environment that results from this placental ischemia is suggested to be an important factor in the development of oxidative stress and a shift in the balance of antiangiogenic and proangiogenic factors, which plays a role in endothelial dysfunction of the placenta and maternal vasculature (10). Previous studies from our laboratory in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia demonstrate that the total population of CD4-positive (CD4 ϩ ) T cells isolated from RUPP spleens and transferred to NP rats causes similar pathology to that seen in RUPP rats (46), demonstrating a role for this population in mediating pathophysiology in response to placental ischemia. Recent data from both clinical and animal model stud...

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The Frequency of Peripheral Blood CD4+ CD25high FoxP3+ and CD4+ CD25− FoxP3+ Regulatory T Cells in Normal Pregnancy and Pre‐Eclampsia

Abstract: Our results indicate that the frequency of conventional and non-conventional Tregs alters simultaneously, and the presence in circulation of both of these Treg subsets is similarly important in the adequate development of pregnancy-specific immune tolerance.

Cited by 78 publications

References 25 publications

Regulatory T‐cell Subpopulations in Severe or Early‐onset Preeclampsia

Regulatory T‐cell Subpopulations in Severe or Early‐onset Preeclampsia

Neutrophils induce proangiogenic T cells with a regulatory phenotype in pregnancy

An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia

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