Ana Teles

Regulatory T cells and their role in pregnancy.

Citation Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy. Am J Reprod Immunol 2010

REVIEW ARTICLE: Regulatory T Cells and Their Role in Pregnancy

Citation Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy. Am J Reprod Immunol 2010

Kinetics of regulatory T cells during murine pregnancy.

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.

Estradiol and Progesterone Regulate the Migration of Mast Cells from the Periphery to the Uterus and Induce Their Maturation and Degranulation

Background Mast cells (MCs) have long been suspected as important players for implantation based on the fact that their degranulation causes the release of pivotal factors, e.g., histamine, MMPs, tryptase and VEGF, which are known to be involved in the attachment and posterior invasion of the embryo into the uterus. Moreover, MC degranulation correlates with angiogenesis during pregnancy. The number of MCs in the uterus has been shown to fluctuate during menstrual cycle in human and estrus cycle in rat and mouse indicating a hormonal influence on their recruitment from the periphery to the uterus. However, the mechanisms behind MC migration to the uterus are still unknown. Methodology/Principal Findings We first utilized migration assays to show that MCs are able to migrate to the uterus and to the fetal-maternal interface upon up-regulation of the expression of chemokine receptors by hormonal changes. By using a model of ovariectomized animals, we provide clear evidences that also in vivo, estradiol and progesterone attract MC to the uterus and further provoke their maturation and degranulation. Conclusion/Significance We propose that estradiol and progesterone modulate the migration of MCs from the periphery to the uterus and their degranulation, which may prepare the uterus for implantation.

Blockage of Heme Oxygenase-1 Abrogates the Protective Effect of Regulatory T Cells on Murine Pregnancy and Promotes the Maturation of Dendritic Cells

Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect fetal antigens from maternal effector cells. Their effect is associated with the up-regulation of tolerance-associated molecules at the fetal-maternal interface. Among these, Heme Oxygenase-1 (HO-1, coded by Hmox1) is of special importance as its blockage correlates with increased abortion rates and its up-regulation positively affects pregnancy outcome. Here, we aimed to investigate whether the protective effect of Treg is mediated by HO-1 in a mouse model. HO-1 blockage by Zinc Protoporhyrin (ZnPPIX) abrogated the protective effect of Treg transfer. We found that HO-1 is important in maintaining maternal dendritic cells (DCs) in an immature state, which contributes to the expansion of the peripheral Treg population. This brings to light one essential pathway through which Treg mediates the semi-allogeneic fetus tolerance.

PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model.

Problem  Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect paternal/fetal antigens from rejection by maternal effector cells. Accordingly, the transfer of Treg obtained from BALB/c‐mated CBA/J females prevents abortion in DBA/2J‐mated animals. The actual mechanism through which Treg mediate their protective effect is still inconclusive. Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) and Programmed cell death 1 (PD‐1) are some of known Treg‐associated molecules; however, their role in Treg‐mediated fetal protection in murine model has not been investigated.

Mast cells rescue implantation defects caused by c-kit deficiency

Various physiologically relevant processes are regulated by the interaction of the receptor tyrosine kinase (c-Kit) and its ligand stem cell factor (SCF), with SCF known to be the most important growth factor for mast cells (MCs). In spite of their traditional role in allergic disorders and innate immunity, MCs have lately emerged as versatile modulators of a variety of physiologic and pathologic processes. Here we show that MCs are critical for pregnancy success. Uterine MCs presented a unique phenotype, accumulated during receptivity and expanded upon pregnancy establishment. KitW-sh/W-sh mice, whose MC deficiency is based on restricted c-Kit gene expression, exhibited severely impaired implantation, which could be completely rescued by systemic or local transfer of wild-type bone marrow-derived MCs. Transferred wild-type MCs favored normal implantation, induced optimal spiral artery remodeling and promoted the expression of MC proteases, transforming growth factor-β and connective tissue growth factor. MCs contributed to trophoblast survival, placentation and fetal growth through secretion of the glycan-binding protein galectin-1. Our data unveil unrecognized roles for MCs at the fetomaternal interface with critical implications in reproductive medicine.

The persistence of paternal antigens in the maternal body is involved in regulatory T-cell expansion and fetal-maternal tolerance in murine pregnancy.

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: 200–208

Control of Uterine Microenvironment by Foxp3+ Cells Facilitates Embryo Implantation

Implantation of the fertilized egg into the maternal uterus depends on the fine balance between inflammatory and anti-inflammatory processes. Whilst regulatory T cells (Tregs) are reportedly involved in protection of allogeneic fetuses against rejection by the maternal immune system, their role for pregnancy to establish, e.g., blastocyst implantation, is not clear. By using 2-photon imaging we show that Foxp3+ cells accumulated in the mouse uterus during the receptive phase of the estrus cycle. Seminal fluid further fostered Treg expansion. Depletion of Tregs in two Foxp3.DTR-based models prior to pairing drastically impaired implantation and resulted in infiltration of activated T effector cells as well as in uterine inflammation and fibrosis in both allogeneic and syngeneic mating combinations. Genetic deletion of the homing receptor CCR7 interfered with accumulation of Tregs in the uterus and implantation indicating that homing of Tregs to the uterus was mediated by CCR7. Our results demonstrate that Tregs play a critical role in embryo implantation by preventing the development of a hostile uterine microenvironment.

Regulatory T Cells are Baby's Best Friends.

Regulatory T cells (Treg) are one of the most and best studied immune cell population during human and murine pregnancy, and there is a general consent about their expansion during pregnancy. However, the identification of new and more reliable Treg markers during the last years resulted in some controversies about the kinetics of various Treg subsets at different pregnancy stages. No doubt exists regarding the importance of Treg for a normal pregnancy as pregnancy complications like spontaneous abortion and preeclampsia could be associated with a reduced Treg number and activity. In future, more attention should be paid to bring established data from the bench to the bedside to force the development of adequate therapies for treatment of pregnancy complications. In this article, we summarize previous and recent data on several aspects of Treg biology during human and murine pregnancy.