Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance

Kahn, Daniel; Baltimore, David

doi:10.1073/pnas.1003909107

Cited by 215 publications

(216 citation statements)

References 23 publications

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“…Maternal Tregs have been studied in the context of healthy and pathologic pregnancies 2, 4, 5, 35. In contrast, very little is known about a potential role of fetal Tregs in pregnancy disorders.…”

Section: Discussionmentioning

confidence: 99%

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Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

Loewendorf

Nguyen

Yesayan

et al. 2015

American J Rep Immunol

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ProblemPreeclampsia affects 3–17% of pregnancies worldwide and has serious consequences for both the mother and the fetus. As maternal–fetal immune tolerance is bidirectional, fetal immunopathology may play a significant role in the pathogenesis of pregnancy disorders. Nevertheless, the impact of preeclampsia on the fetal immune system is unclear.Method of studyIn this case–control study, we examined the phenotype of innate and adaptive immune cells from the cord blood of 3rd trimester babies born to healthy mothers and compared them to cord blood from 3rd trimester babies born to mothers with symptomatic preeclampsia.ResultsThe ratio of CD56hi CD16− non‐activated/regulatory NK cells to CD56lo CD16+ activated/effector NK cells as well as the proportion of CD4+ T cells was significantly decreased in the cord blood of babies born to preeclamptic mothers. The percentage of FoxP3+ Treg, especially the FoxP3lo populations (resting Treg and cytokine Treg), were significantly reduced. Importantly, this reduction in FoxP3+ Treg affected the ratio of CD8+ effector T cells per FoxP3+ Treg in the cord blood of babies born to preeclamptic mothers.ConclusionThese observations indicate that there are significant fetal immune system derangements during preeclampsia.

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Section: Discussionmentioning

confidence: 99%

“…To cope with these significant antigenic differences, mechanisms of immune tolerance are invoked during pregnancy 2, 4, 5. Among these are the actions of the powerful T regulatory (Treg) cell that has the ability to negatively regulate major portions of the cellular immune system 6.…”

Section: Introductionmentioning

confidence: 99%

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

Loewendorf

Nguyen

Yesayan

et al. 2015

American J Rep Immunol

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“…However, establishment of fetomaternal tolerance itself, reflected by reproductive success, did not depend on the presence of GR in T cells. Although Treg-driven tolerance has been shown to be fetal antigen specific in the first place (22), it has also been noted that Tregs are able to suppress T-cell responses to unrelated antigens in the form of a bystander suppression (50). This can have detrimental consequences as Treg expansion leaves pregnant mice more prone to infections with certain pathogens including Listeria and Salmonella species, whereas Treg depletion has been shown to restore host defense (23).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy

Engler

Kursawe

Solano

et al. 2017

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

123

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Pregnancy is one of the strongest inducers of immunological tolerance. Disease activity of many autoimmune diseases including multiple sclerosis (MS) is temporarily suppressed by pregnancy, but little is known about the underlying molecular mechanisms. Here, we investigated the endocrine regulation of conventional and regulatory T cells (Tregs) during reproduction. In vitro, we found the pregnancy hormone progesterone to robustly increase Treg frequencies via promiscuous binding to the glucocorticoid receptor (GR) in T cells. In vivo, T-cell-specific GR deletion in pregnant animals undergoing experimental autoimmune encephalomyelitis (EAE), the animal model of MS, resulted in a reduced Treg increase and a selective loss of pregnancy-induced protection, whereas reproductive success was unaffected. Our data imply that steroid hormones can shift the immunological balance in favor of Tregs via differential engagement of the GR in T cells. This newly defined mechanism confers protection from autoimmunity during pregnancy and represents a potential target for future therapy.multiple sclerosis | autoimmunity | pregnancy | Treg | steroid hormones R eproduction is fundamental to the maintenance and evolution of species. To ensure successful pregnancy, mothers have to establish robust immunological tolerance toward the semiallogeneic conceptus providing a secure niche for fetal development. Multiple mechanisms have evolved to prevent fetus-directed immune responses and alloreactive infiltration of the fetomaternal interface (1). These include creating a privileged local microenvironment that hampers T-cell priming and infiltration (2-4) but also imply global modulation of the immune system by pregnancy hormones and the shedding of fetal antigen into the mothers circulation (5).Intriguingly, pregnancy is also well known to suppress the inflammatory activity of a number of cell-mediated autoimmune diseases, including rheumatoid arthritis (6, 7), autoimmune hepatitis (8), and multiple sclerosis (MS) (9, 10). However, this beneficial effect is limited to the period of gestation and usually followed by a rebound of disease activity postpartum. In the case of MS, third trimester pregnancy leads to a remarkable reduction of the MS relapse rate (11), which exceeds the effects of most currently available disease-modifying drugs. Similarly, pregnancy as well as treatment with pregnancy hormones protect rodents from experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS (12) in both SJL/J and C57BL/6 mice (13-16), underpinning an interaction between pregnancy-related immune and endocrine adaptations and central nervous system (CNS) autoimmunity (17).The sensitive balance between conventional effector T cells (Tcons) and regulatory T cells (Tregs) has transpired as a common theme that connects reproductive biology and autoimmunity on a mechanistic level (18)(19)(20)(21). Tregs are characterized by the transcription factor forkhead box P3 (Foxp3) and effectively control effector responses mounted by Tcons in...

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“…Although elegant studies in mice have shown the presence of maternal T cells specific for paternal transgenes (i.e., actin-OVA and actin-2W1S; refs. 20, 21) or for male antigens (22), the nature of the tissue targeted by maternal effector T cells cannot be defined, since the paternally inherited genes are assumed to be present in both trophoblast cells and fetus. In humans, trophoblast-specific T cells are likely to be HLA-C restricted, as this is the only polymorphic trophoblast HLA class I molecule.…”

Section: T Cells In Pregnancymentioning

confidence: 99%

Uterine NK cells: active regulators at the maternal-fetal interface

Moffett¹,

Colucci²

2014

J. Clin. Invest.

338

301

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Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternalfetal immune mechanism that regulates placentation. The maternal-fetal interface in the uterusThe immunological paradox of pregnancy became a central preoccupation of immunologists after the discovery of acquired immunological tolerance (1). Pregnancy and transplantation were instrumental in the discovery of MHC polymorphisms, since the best natural producers of alloantibodies against HLA molecules are multiparous women (2) and polytransfused individuals (3). Since Medawar's influential essay (4), the focus for immunologists has been how maternal T cells become tolerant of the fetal allograft. The current state of this field has been summarized in recent scholarly reviews (5, 6). We have taken a different approach that arose from studying pregnancy disorders, which affect millions of women and are a persistent global health problem. This view of the maternal immune system arose from considering how placentation evolved in mammals and is centered on the anatomy, physiology, and pathology of the pregnant uterus. We focus on the immune cells present in the pregnant uterine lining, the decidua, dominated by NK cells (known as decidual NK cells or uterine NK

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Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance

Cited by 215 publications

References 23 publications

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

Preeclampsia is Characterized by Fetal NK Cell Activation and a Reduction in Regulatory T Cells

Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy

Uterine NK cells: active regulators at the maternal-fetal interface

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