Regulatory T cells and the immune pathogenesis of prenatal infection (original) (raw)
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Reproductive biology and endocrinology : RB&E, 2003
The adaptive immune system of placental mammals has evolved to tolerate the fetus. Rejection of the fetus by adaptive immune responses is therefore a rare event, with abortion being caused more frequently by inflammation in the placenta. This review will cover recent aspects of immune privilege and the innate immune system at the feto-maternal interface, citing examples of the role played by microbial infections in fetal demise.
Immune mechanisms at the maternal-fetal interface: perspectives and challenges
Nature Immunology, 2015
in the fields of Reproductive Biology and Immunology to assess the state of the science regarding maternal-fetal immunity and to discuss current knowledge gaps, identify challenges and outline future research directions. This Commentary discusses the seminal outcomes and recommendations from the workshop.
Immune cells and molecules in pregnancy: friends or foes to the fetus?
Expert Review of Clinical Immunology, 2006
Considering allograft rejection as a basic feature of the immune system, the mammalian pregnancy is an immunological paradox where the semi-allogeneic fetus is not rejected. How are the demands of pregnancy solved in the context of maternal immunity? Medawar's original proposal of maternal immune inertness during pregnancy should be revised to active materno-placental tolerance. Multiple mechanisms are involved in peripheral and local tolerance induction that prevents fetal rejection while maintaining competent immune surveillance and protection. The goal of this review is to discuss the major cellular and molecular components of the immune system that control and promote fetal survival.
Regulatory T cells induce a privileged tolerant microenvironment at the fetal-maternal interface
European Journal of Immunology, 2006
The mechanisms underlying immune tolerance during pregnancy are poorly understood. In this regard, Treg seem to play an important role in mediating maternal tolerance to the fetus. We proposed a crucial role of T regulatory cells (Treg) in avoiding immunological rejection of the fetus after observing diminished number and function of Treg in abortion-prone mice. We further confirmed the protective role of Treg during pregnancy by transferring pregnancy-induced Treg into abortion-prone mice, which prevented rejection. Here, we analyzed the mechanisms involved in Treg-mediated protection. As expected, Treg therapy prevented abortion, while expanding the peripheral and thymic Treg population. Surprisingly, the decidual levels of the Th1 cytokines IFN-c and TNF-a were not diminished after therapy. Interestingly, the mRNA levels of leukemia inhibitory factor, TGF-b and heme oxygenase-1 at the fetal-maternal interface were dramatically up-regulated after Treg transfer, while the levels of indolamine 2,3-dioxygenase remained unchanged. Our data suggest that Treg treatment can not prevent T cell infiltration or high Th1 levels but is able to create a privileged tolerant microenvironment at the fetal-maternal interface, further shedding light onto the molecular mechanisms involved in pregnancy tolerance.
Cell Reports
During pregnancy, maternal regulatory T cells (Tregs) are important in establishing immune tolerance to invading fetal extravillous trophoblasts (EVTs). CD25 HI FOXP3+ Tregs are found at high levels in decidual tissues and have been shown to suppress fetus-specific and nonspecific responses. However, limited data are available on additional decidual Treg types and the mechanisms by which they are induced. This study investigated three distinct decidual CD4+ Treg types in healthy pregnancies with a regulatory phenotype and the ability to suppress T cell responses: CD25 HI FOXP3+, PD1 HI IL-10+, and TIGIT+FOXP3 dim . Moreover, co-culture of HLA-G+ EVTs or decidual macrophages with blood CD4+ T cells directly increased the proportions of CD25 HI FOXP3+ Tregs compared to T cells cultured alone. EVTs also increased PD1 HI Tregs that could be inhibited by HLA-C and CD3 antibodies, suggesting an antigen-specific induction. The presence of distinct Treg types may allow for the modulation of a variety of inflammatory responses in the placenta.
Gestationally-Dependent Immune Organization at the Maternal-Fetal Interface
SSRN Electronic Journal, 2021
The immune system and placenta have a dynamic relationship across gestation to accommodate fetal growth and development. High-resolution characterization of this maternalfetal interface is necessary to better understand the immunology of pregnancy and its complications. We developed a single-cell framework to simultaneously immuno-phenotype circulating, endovascular, and tissue-resident cells at the maternal-fetal interface throughout gestation, discriminating maternal and fetal contributions. Our data reveal distinct immune profiles across the endovascular and tissue compartments with tractable dynamics throughout gestation that respond to a systemic immune challenge in a gestationally-dependent manner. We uncover that mononuclear phagocytes and neutrophils drive the temporal immune composition of the placenta with remarkably diverse populations, including PD-L1-expressing subsets having compartmental and early gestational bias. Our approach and accompanying datasets provide a resource for additional investigations into gestational immunology and evoke a more significant role for the innate immune system in establishing the microenvironment of early pregnancy. .
PLoS ONE, 2014
Pregnancy poses a unique challenge to the human immune system: the semi-allogeneic fetus must be protected from maternal immune attack while immunity towards pathogens is maintained. Breakdown in maternal-fetal tolerance can lead to pregnancy-specific diseases with potentially high degrees of morbidity and mortality for both the mother and her fetus. Various immune cell-types could mediate these functions, but a comprehensive evaluation of the peripheral and local maternal T cell and regulatory T cell compartments in normal human pregnancy is lacking. In this case-control study, we apply the Human Immunology Project Consortium proposed gating strategies to samples from healthy 3 rd trimester human subjects compared with healthy non-pregnant controls. The proportions of HLA-DR+ and CD38+ effector-and effector memory CD8 T cells are significantly increased in the peripheral blood of pregnant women. Utilizing a novel technique that takes advantage of the standard protocol for intrauterine cleanup after cesarean section, we isolate lymphocytes resident at the uteroplacental interface (UPI). At the UPI, the CD4 and CD8 T cell compartments largely mirror the peripheral blood, except that the proportion of HLA-DR+ activated T regulatory cells is significantly increased in direct proportion to an observed increase in the number of activated CD8 T cells. We find that cryopreservation and delayed sample processing (. 12 hours) decreases our ability to identify regulatory T cell subsets. Further, the Consortium proposed method for Treg identification underrepresents Resting and Cytokine Tregs compared with Activated Tregs, thus skewing the entire population. Better understanding of the changes in the immune system during pregnancy in the peripheral blood and at the uteroplacental interface are essential for progress in treatment of pregnancy diseases such as pre-eclampsia and recurrent miscarriage.
The Lancet Infectious Diseases, 2012
Chronic infections during pregnancy are highly prevalent in some parts of the world. Infections with helminths, Trypanosoma cruzi, Plasmodium spp, and HIV might aff ect the development of fetal immunity and susceptibility to postnatal infections independently of in-utero transmission of the pathogens. Fetal adaptive immune responses are common in neonates who have been exposed to maternal infection during pregnancy but not infected themselves. Such responses could aff ect the development of immunity to the homologous pathogens and their control during the fi rst few years of life. Fetal innate and regulatory responses might also aff ect immunity to unrelated pathogens and responses to vaccines. Strategies to improve child health should integrate the possible clinical implications of in-utero exposure to chronic maternal infections.
Regulatory T-Cells in Pregnancy: Historical Perspective, State of the Art, and Burning Questions
Frontiers in Immunology, 2014
In this review, we first revisit the original concept of "suppressor T-cells" in pregnancy, put it in a historical perspective, and then highlight the main data that licensed its resurrection and revision into the concept of "regulatory T-cells" (Tregs) in pregnancy. We review the evidence for a major role of Tregs in murine and human pregnancy and discuss Treg interactions with dendritic and uterine natural killer cells, other players of maternal-fetal tolerance. Finally, we highlight what we consider as the most important questions in the field.