Understanding the function of T cells at the maternal-fetal interface remains one of the most difficult problems in reproductive immunology. A great deal of work over the last two decades has led to the view that the T cells that populate the decidua have important roles in both normal and pathological pregnancies, but the exact nature of these roles has remained unclear. Indeed, the old assumption that decidual T cells are uniformly threatening to fetal survival because the placenta is fundamentally an 'allograft' has given way to the idea that different T cell subsets contribute in different ways to pregnancy success or failure. Accordingly, some T cells are thought to protect the placenta from immune rejection and facilitate embryo implantation, while others are thought to contribute to pregnancy pathologies such as preeclampsia and spontaneous abortion. Here, we review the current state of information on the behavior of decidual T cells with a focus on both mouse and human studies, and with an emphasis on the many unresolved areas within this overall emerging framework.

The chemokine-mediated recruitment of effector T cells to sites of inflammation is a central feature of the immune response. The extent to which chemokine expression levels are limited by the intrinsic developmental characteristics of a tissue has remained unexplored. We show in mice that effector T cells cannot accumulate within the decidua, the specialized stromal tissue encapsulating the fetus and placenta. Impaired accumulation was in part attributable to the epigenetic silencing of key T cell-attracting inflammatory chemokine genes in decidual stromal cells, as evidenced by promoter accrual of repressive histone marks. These findings give insight into mechanisms of fetomaternal immune tolerance, as well as reveal the epigenetic modification of tissue stromal cells as a modality for limiting effector T cell trafficking.

Uncovering the causes of pregnancy complications such as preterm labor requires greater insight into how the uterus remains in a noncontractile state until term and then surmounts this state to enter labor. Here, we show that dynamic generation and erasure of the repressive histone modification tri-methyl histone H3 lysine 27 (H3K27me3) in decidual stromal cells dictate both elements of pregnancy success in mice. In early gestation, H3K27me3-induced transcriptional silencing of select gene targets ensured uterine quiescence by preventing the decidua from expressing parturition-inducing hormone receptors, manifesting type 1 immunity, and most unexpectedly, generating myofibroblasts and associated wound-healing responses. In late gestation, genome-wide H3K27 demethylation allowed for target gene upregulation, decidual activation, and labor entry. Pharmacological inhibition of H3K27 demethylation in late gestation not only prevented term parturition, but also inhibited delivery while maintaining pup viability in a noninflammatory model of preterm parturition. Immunofluorescence analysis of human specimens suggested that similar regulatory events might occur in the human decidua. Together, these results reveal the centrality of regulated gene silencing in the uterine adaptation to pregnancy and suggest new areas in the study and treatment of pregnancy disorders.