Effector and Activated T Cells Induce Preterm Labor and Birth That Is Prevented by Treatment with Progesterone

Abstract

Preterm labor commonly precedes preterm birth, the leading cause of perinatal morbidity and mortality worldwide. Most research has focused on establishing a causal link between innate immune activation and pathological inflammation leading to preterm labor and birth. However, the role of maternal effector/activated T cells in the pathogenesis of preterm labor/birth is poorly understood. In this study, we first demonstrated that effector memory and activated maternal T cells expressing granzyme B and perforin are enriched at the maternal-fetal interface (decidua) of women with spontaneous preterm labor. Next, using a murine model, we reported that prior to inducing preterm birth, in vivo T cell activation caused maternal hypothermia, bradycardia, systemic inflammation, cervical dilation, intra-amniotic inflammation, and fetal growth restriction, all of which are clinical signs associated with preterm labor. In vivo T cell activation also induced B cell cytokine responses, a proinflammatory macrophage polarization, and other inflammatory responses at the maternal-fetal interface and myometrium in the absence of an increased influx of neutrophils. Finally, we showed that treatment with progesterone can serve as a strategy to prevent preterm labor/birth and adverse neonatal outcomes by attenuating the proinflammatory responses at the maternal-fetal interface and cervix induced by T cell activation. Collectively, these findings provide mechanistic evidence showing that effector and activated T cells cause pathological inflammation at the maternal-fetal interface, in the mother, and in the fetus, inducing preterm labor and birth and adverse neonatal outcomes. Such adverse effects can be prevented by treatment with progesterone, a clinically approved strategy.

Influenza-Induced Interferon Lambda Response Is Associated With Longer Time to Delivery Among Pregnant Kenyan Women

“…This is consistent with the idea that baseline inflammation can blunt responses to stimuli (61). In fact, this could be entirely consistent with the inflammatory signatures identified in earlier studies (5,(17)(18)(19)(20)(21)(22)(23)(24), all of which were performed in the absence of an exogenous stimulus.…”

“…For instance, elevated expression of the inflammatory cytokine tumor necrosis factor (TNF) in the amniotic fluid was associated with both infection and preterm birth (17). A recent study demonstrated that activated T cells are found at the maternal-fetal interface in women with spontaneous preterm delivery, and that, in a mouse model, treatment with progesterone can attenuate this inflammation and reduce risk of preterm birth (18).…”

Single Cell Transcriptional Signatures of the Human Placenta in Term and Preterm Parturition

“…Importantly, at 24-34 weeks of gestation, we found that the single cell signatures of macrophages, monocytes, activated T cells, and fibroblasts were increased in the circulation of women with preterm labor and delivery compared to gestational age-matched controls (Figure 4E and S19B). These findings are in line with previous reports indicating a role for these immune cell-types in the pathophysiology of preterm labor 29, 66–68 .…”

“…Other genes highly expressed by LED cells were CD34, CDH5, EDNRB, PDPN, and TIE1 (Figure 2C, S7). This finding conclusively shows the presence of lymphatic vessels in the decidua parietalis of the chorioamniotic membranes, providing a major route for maternal T cells infiltrating the maternal-fetal interface 29 .…”

Are B cells altered in the decidua of women with preterm or term labor?

“…Yet, several studies reported strong evidence that T cells, the primary cellular component of the adaptive immune system, are present at the maternal‐fetal interface . More recently, we provided evidence indicating that T cells are also implicated in the mechanisms that lead to labor at term and spontaneous preterm labor . However, the main humoral component of adaptive immunity, B cells, has been less investigated in the context of labor at term or preterm labor.…”