Monocytes in pregnancy and preeclampsia

American Journal of Reproductive Immunology, 2010

Regulatory T cells emerge in the last years as key players in allowing fetal survival within the maternal uterus. They were shown to be a unique subpopulation of T cells expanding during human and murine pregnancy. The importance of Treg for a normal pregnancy situation was proven by studies showing that their absence impairs murine pregnancy while the adoptive transfer of Treg prevents fetal rejection. In humans, pregnancy pathologies are associated with lower Treg frequencies while therapies that improve pregnancy outcome are able to boost their number. Functional studies have shown that Treg can regulate immune cell responses directly at the fetal-maternal interface either by interacting with other cells or by inducing the expression of immune regulatory molecules. This article revises relevant literature on regulatory T cells in human and murine pregnancy.

Biology of …, 2010

The Journal of Immunology, 2009

Regulatory T cells (Treg) expand during pregnancy and are present at the fetal-maternal interface at very early stages in pregnancy. The migration mechanisms of Treg to the pregnant uterus are still unclear. Human chorionic gonadotropin (hCG) is secreted by the blastocyst immediately after fertilization and has chemoattractant properties. Therefore, we sought to analyze whether hCG secreted by early trophoblasts attracts Treg to the uterus and hence contributes to maternal tolerance toward the fetus. Decidua and placenta tissue samples from patients having spontaneous abortions or ectopic pregnancies were employed to evaluate Treg and hCG levels. Age-matched samples from normal pregnant women served as controls. We further performed in vitro studies with primary first trimester trophoblast cells and a choriocarcinoma cell line (JEG-3) aiming to evaluate the ability of secreted hCG to attract Treg. Patients having miscarriages or ectopic pregnancy presented significantly decreased hCG mRNA and protein levels associated with decreased Foxp3, neuropilin-1, IL-10, and

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.

Nature Immunology, 2015

Leaders gathered at the US National Institutes of Health in November 2014 to discuss recent advances and emerging research areas in aspects of maternal-fetal immunity that may affect fetal development and pregnancy success. Pregnancy is a unique situation in which the mother and the hemiallogeneic fetus peacefully coexist. Numerous fetal, maternal and placental mechanisms work in concert to protect the fetus from immunological recognition and rejection. During human placentation, several changes occur in the uterus. First, the stromal compartment of the endometrium differentiates into the decidua. Second, placental villous trophoblasts (PVTs) of fetal origin traverse the uterine epithelium and invade the decidua as well as the inner third of the myometrium. Third, the trophoblast differentiates, and fetal extravillous trophoblasts (EVTs) penetrate and extensively remodel uterine arteries. During this process they replace the endothelium and (partially) the muscle layer of these vessels. To a much lesser extent, the same process occurs in uterine veins. A successful pregnancy involves complex interactions between fetal trophoblasts and maternal decidual immune cells, which allow the embryo and then fetus to develop in the uterus while the mother's immune system remains largely intact. Uterine natural killer (uNK) cells, immature dendritic cells (iDCs), T cells and macrophages contribute to modulating the uterine environment to sustain a successful pregnancy.

American Journal of Reproductive Immunology, 2010

Citation Zenclussen ML, Thuere C, Ahmad N, Wafula PO, Fest S, Teles A, Leber A, Casalis PA, Bechmann I, Priller J, Volk H-D, Zenclussen AC. The persistence of paternal antigens in the maternal body is involved in regulatory T-cell expansion and fetal-maternal tolerance in murine pregnancy. Am J Reprod Immunol 2010; 63: 200–208Problem Mammalian pregnancy is a state of immunological tolerance and CD4+ CD25+ regulatory T cells (Treg) contribute to its maintenance. Knowing that Treg act in an antigen-specific way during pregnancy, we hypothesized that they are generated after maternal immune cells encounter paternal antigens.Method of study We mated wild type females with transgenic green fluorescent protein (GFP) males in an allogenic setting and killed them on different days of pregnancy.Results Presence of paternal and maternal MHC class II+ cells in vaginal lavage on day 0.5 of pregnancy was confirmed. Thus, antigen presentation may take place early during pregnancy in the periphery either by the direct or indirect pathways. Foxp3+ cells known to have regulatory activity could be detected on day 2 of pregnancy in lymph nodes and shortly after implantation at the fetal-maternal interface.Conclusion Our data suggest that paternal antigens are processed early during pregnancy, which leads to the generation of Treg. The continuous release of placental antigens into the maternal circulation allows the maintenance of a Treg population which is specific for paternal antigens and mediates tolerance toward the semi-allogeneic fetus until the time point of birth.

American Journal of Reproductive Immunology, 2010

Citation Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy. Am J Reprod Immunol 2010Regulatory T cells emerge in the last years as key players in allowing fetal survival within the maternal uterus. They were shown to be a unique subpopulation of T cells expanding during human and murine pregnancy. The importance of Treg for a normal pregnancy situation was proven by studies showing that their absence impairs murine pregnancy while the adoptive transfer of Treg prevents fetal rejection. In humans, pregnancy pathologies are associated with lower Treg frequencies while therapies that improve pregnancy outcome are able to boost their number. Functional studies have shown that Treg can regulate immune cell responses directly at the fetal–maternal interface either by interacting with other cells or by inducing the expression of immune regulatory molecules. This article revises relevant literature on regulatory T cells in human and murine pregnancy.

American Journal of Reproductive Immunology, 2007

Problem The semi-allogeneic fetus is usually tolerated by the maternal immune system. This was proposed to be modulated by CD4+CD25+foxp3+ regulatory T cells (Treg). We aimed to determine the kinetics of Treg during murine gestation and investigate whether changes in Treg levels respond to hormonal variations during pregnancy or generated changes in the local indolamine dioxygenase (IDO) expression.Method of study We included in our studies the well-known CBA/J × DBA/2J abortion-prone combination using CBA/J × BALB/c as controls. CBA/J × C57/BL6 and BALB/c × C57/BL6 were included as further controls. Animals were killed on days 0, 2, 5, 8, 10, and 12 of pregnancy to measure the levels of Treg, pregnancy-related hormones and IDO expression.Results A Treg augmentation in normal pregnancy combinations could be observed on day 2 in several organs contrary to the observations made in abortion-prone mice. No differences in hormonal levels could be seen among all groups. IDO was expressed exclusively in placenta starting from day eight, showing no variations among the groups.Conclusion Differences in Treg levels and pregnancy outcome do not correlate with changes in hormonal levels. In addition, as Treg augmentation takes place early and it is observed mainly in the decidual component of the fetal–maternal interface, IDO does not seem to be the pathway underlying Treg protective activity as proposed for humans.

American Journal of Reproductive Immunology, 2012

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.

American Journal of Reproductive Immunology, 2005

Mx proteins are 70-80 kD intracellular antiviral proteins induced by viruses and type I interferons (IFNs). Mx proteins belong to the dynamin superfamily of large GTPases, thought to regulate endocytosis, intracellular vesicle trafficking and cytokinesis. Although antiviral Mx proteins are highly inducible during early pregnancy by embryo-derived IFN tau, cellular functions of Mx proteins in uninduced cells are poorly defined. To better understand the physiological role of Mx proteins during early pregnancy, expression and localization of ovine Mx1 (oMx1) protein were determined in a uterine derived cell line (oGE). oMx1 and beta tubulin were immunolabeled in cells at different stages of the cell cycle. oMx1 was uniformly distributed in the cytoplasm during interphase in the absence of roIFN tau, whereas oMx1 aggregated around vacuoles near the surface of the cells in the presence of roIFN. Interestingly, oMx1 co-localized with mitotic spindles during metaphase. During telophase, oMx1 co-localized with remnants of mitotic spindles at intercellular bridges between dividing cells. Our findings are consistent with a role for Mx1 in secretion by oGE cells and indicate that oMx1 may be involved in cell division.

American Journal of Reproductive Immunology, 2010

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.

HLA: Immune Response Genetics, 2020

Immunology Today, 1997