Maternal and fetal T cells in term pregnancy and preterm labor

Abstract

Pregnancy is a state of immunological balance during which the mother and the developing fetus must tolerate each other while maintaining sufficient immunocompetence to ward off potential threats. The site of closest contact between the mother and fetus is the decidua, which represents the maternal-fetal interface. Many of the immune cell subsets present at the maternal-fetal interface have been well described; however, the importance of the maternal T cells in this compartment during late gestation and its complications, such as preterm labor and birth, has only recently been established. Moreover, pioneer and recent studies have indicated that fetal T cells are activated in different subsets of preterm labor and may elicit distinct inflammatory responses in the amniotic cavity, leading to preterm birth. In this review, we describe the established and proposed roles for maternal T cells at the maternal-fetal interface in normal term parturition, as well as the demonstrated contributions of such cells to the pathological process of preterm labor and birth. We also summarize the current knowledge of and proposed roles for fetal T cells in the pathophysiology of the preterm labor syndrome. It is our hope that this review provides a solid conceptual framework highlighting the importance of maternal and fetal T cells in late gestation and catalyzes new research questions that can further scientific understanding of these cells and their role in preterm labor and birth, the leading cause of neonatal mortality and morbidity worldwide.

Keywords: adaptive immunity; amniotic fluid; decidua; maternal-fetal interface; parturition.

Fig. 1

Maternal T cells at the maternal–fetal interface in term pregnancy and preterm labor/birth. (Left panel) During normal pregnancy, a suppressive microenvironment exists at the maternal–fetal interface to prevent aberrant maternal immune responses against foreign antigens. This suppressive microenvironment is mainly driven by regulatory T cells and exhausted T cells. (Right panel) Preterm labor is accompanied by inflammation at the maternal–fetal interface, which can be driven or exacerbated by the invasion of activated effector T cells that release pro-inflammatory mediators such as perforin and granzyme B. Moreover, local inflammation may lead to the reactivation of exhausted T cells, restoring effector functions such as the release of pro-inflammatory cytokines and thereby further propagating T-cell responses

Fig. 2

Fetal T cells in preterm labor subsets and term gestation. (Upper left panel) Intra-amniotic infection/inflammation-associated preterm labor and birth are accompanied by the activation of conventional CD4+ and CD8+ T cells by microbial products, resulting in the release of pro-inflammatory cytokines. (Upper right panel) A subset of idiopathic preterm labor cases (preterm labor occurring in the absence of clinical intra-amniotic infection/inflammation) are associated with an increased number of activated fetal CD4+ T cells in amniotic fluid together with elevated concentrations of T-cell cytokines. (Lower left panel) In term pregnancy, fetal immunity is skewed toward a tolerant state, as evidenced by an elevated propensity for fetal naïve T cells to differentiate into regulatory T cells (Tregs). (Lower right panel) Fetal T cells in the amniotic cavity express a phenotype similar to that of intra-epithelial lymphocytes in the intestines, suggesting that some T cells in this compartment are derived from the mucosal organs that are in contact with amniotic fluid