Alterations in the Expression of Homing-Associated Molecules at the Maternal/Fetal Interface During the Course of Pregnancy1

Abstract

One of the most fascinating immunologic questions is how the genetically distinct fetus is able to survive and develop within the mother without provoking an immune rejection response. The pregnant uterus undergoes rapid morphological and functional changes, and these changes may influence the nature of local immune responses at the maternal/fetal interface at different stages of gestation. We hypothesized that specialized mechanisms exist to control access of maternal leukocyte subsets to the decidua and that these mechanisms are modulated during the course of pregnancy. At the critical period of initial placenta development, the maternal/fetal interface displays an unparalleled compartmentalization of microenvironmental domains associated with highly differentiated vessels expressing vascular addressins in nonoverlapping patterns and with recruitment of specialized leukocyte subsets (monocytes, granulated metrial gland cells, and granulocytes) thought to support, modulate, and regulate trophoblast invasion. One of the most striking observations at this time of gestation is the almost complete exclusion of lymphocytes from the maternal/fetal interface. The second half of pregnancy is characterized by a partial loss of microenvironmental specialization and different switches in vascular specificity within the decidua basalis, paralleling dramatic changes in the populations of recruited leukocytes (e.g., a striking influx of lymphocytes, especially T cells). In the term pregnant uterus, the expression of all vascular addressins decreased dramatically; only weakly staining maternal vascular segments remained. These segments may define sites of extremely low residual traffic in the term decidua, which contains remarkably few maternal leukocytes overall. Our results suggest that the maternal/fetal interface represents a situation in which leukocyte trafficking is exquisitely regulated to allow entry of specialized leukocyte subsets that may play a fundamental role in immune regulation during pregnancy.

Functional involvement of P‐selectin and MAdCAM‐1 in the recruitment of α4β7‐integrin‐expressing monocyte‐like cells to the pregnant mouse uterus

“…Short-term homing studies using defined cell lines expressing known homing receptors may permit evaluation of the ability of particular adhesion pathways to participate in leukocyte interaction and arrest in decidual vessels. As recently described [10], injection of the TRITC-labeled a4b7 hi LFA-1 + cell line TK1 into pregnant BALB/c mice in presence or absence of blocking mAb against MAdCAM-1 clearly demonstrated that vascular MAdCAM-1 is functional, supporting the importance of this vascular adhesion receptor in the localization observed. Alternatively, the rapid pace of fetal and placental development in the mouse, with most of the immunologically critical events occurring within the first 2 weeks, makes it possible to carry out "poorman's knockout experiments" using mAb to inhibit the contribution of target adhesion pathways or to deplete antigenetically defined leukocyte subsets.…”

“…The expression of homing-associated molecules at the maternal/fetal interface of normal pregnancies was described recently [9,10]. This study will focus on the unusual co-expression of MAdCAM-1 and P-selectin observed on maternal vessels of the vascular zone at day 9 of gestation and on the functional involvement of these vascular addressins in leukocyte traffic to the decidua basalis.…”

“…Antibodies directed against MAdCAM-1 do not inhibit the recruitment of b7 + Mac-1 -cells. Importantly, at midgestation the dilated maternal vessels of the vascular zone, which display again a combined expression of MAdCAM-1 and P-selectin, now additionally stain weakly but significantly with anti-VCAM-1 mAb [10]. VCAM-1, which represents the ligand for a4b1-integrin, can also mediate adhesion through activated a4b7-integrin [12].…”

“…It is appropriate to emphasize that the decidua represents a highly complex tissue in which leukocyte trafficking needs to be exquisitely regulated to allow entry of specialized subsets hypothesized to support and reg- [DOI 10.1002/eji.200425223] ulate trophoblast invasion and local immune responses. The highly regulated expression of vascular addressins in the decidua may be fundamental to this process [9,10].…”

Choriodecidual leukocytes display a unique gene expression signature in spontaneous labor at term

“…Collectively, these data suggest that the chorioamniotic membranes, and most likely the decidual stromal cells, recruit maternal circulating leukocytes into the choriodecidua prior to and during the process of labor. Following recruitment, the choriodecidual leukocytes expressed cell adhesion molecules (CAMs) [16,[31][32][33] and labor mediators including cytokines/chemokines [14][15][16]34] and matrix metalloproteinases (MMPs) [35]. All of which elicit cellmediated immune responses that participate in the process of labor [1,[36][37][38].…”