Fetal T Cell Activation in the Amniotic Cavity during Preterm Labor: A Potential Mechanism for a Subset of Idiopathic Preterm Birth

Abstract

Prematurity is the leading cause of perinatal morbidity and mortality worldwide. In most cases, preterm birth is preceded by spontaneous preterm labor, a syndrome that is associated with intra-amniotic inflammation, the most studied etiology. However, the remaining etiologies of preterm labor are poorly understood; therefore, most preterm births are categorized as idiopathic. In this study, we provide evidence showing that the fetal immune system undergoes premature activation in women with preterm labor without intra-amniotic inflammation, providing a potential new mechanism of disease for some cases of idiopathic preterm birth. First, we showed that fetal T cells are a predominant leukocyte population in amniotic fluid during preterm gestations. Interestingly, only fetal CD4 + T cells were increased in amniotic fluid of women who underwent idiopathic preterm labor and birth. This increase in fetal CD4 + T cells was accompanied by elevated amniotic fluid concentrations of T cell cytokines such as IL-2, IL-4, and IL-13, which are produced by these cells upon in vitro stimulation, but was not associated with the prototypical cytokine profile observed in women with intra-amniotic inflammation. Also, we found that cord blood T cells, mainly CD4 + T cells, obtained from women with idiopathic preterm labor and birth displayed enhanced ex vivo activation, which is similar to that observed in women with intra-amniotic inflammation. Finally, we showed that the intra-amniotic administration of activated neonatal CD4 + T cells induces preterm birth in mice. Collectively, these findings provide evidence suggesting that fetal T cell activation is implicated in the pathogenesis of idiopathic preterm labor and birth.

Amniotic fluid cell-free transcriptome: a glimpse into fetal development and placental cellular dynamics during normal pregnancy

“…Of all the factors previously reported to be reflected in the AF transcriptome, advancing gestation seems to have the most dramatic effect on the AF transcriptome considering the number of genes differentially expressed. AF gene expression changes with gestational age have been associated with cell types found in the intrauterine environment and with the development of multiple organ systems [78,85,98,103]. These results point to the possible use of the AF transcriptome to complement fetal lung maturity evaluation [85,98] when elective delivery prior to term is considered, and also to discover biomarkers for the 'great obstetrical syndromes' [104].…”

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

“…As mentioned above, inflammation has been linked to the pathogenesis of idiopathic PTB, and also other pregnancy complications in mice and humans [7,[50][51][52][53][54][55]. Furthermore, PTB is considered to have early pregnancy origins, prior to placental development.…”

“…Also, IL8 (CXCL8) drives major T cell effector function in human newborns, as it allows for the activation of antimicrobial neutrophils and γδ T cells [ 135 ]. Importantly, these mechanisms may already instruct fetal immunity prior to birth during pregnancy and their dysregulation could be involved in the pathogenesis of PTB [ 53 , 54 , 134 ].…”

“…Emerging data arising from humans and mice also indicate that the fetal environment in PTB is also characterized by inflammation, along with the priming of fetal T cells against maternal antigens [ 54 ]. Activated fetal T cells are also found in the amniotic cavity and are increased in cases with chorioamnionitis [ 53 ]. Future studies are needed to confirm if fetal inflammation is the cause of the maternal inflammation and related PTB, or the consequence of the maternal spill-over of inflammatory cytokines.…”

Cellular immune responses in amniotic fluid of women with preterm prelabor rupture of membranes

“…Amniotic fluid contains a diverse array of innate and adaptive immune cells that vary as normal gestation progresses [49]. Specifically, neutrophils, monocytes/macrophages, T cells, innate lymphoid cells, natural killer (NK) cells, and B cells are present in the amniotic cavity of women with a normal pregnancy [49][50][51]. These cellular immune responses are augmented in women with pregnancy complications such as preterm labor with intact membranes [52], clinical chorioamnionitis at term [53], and preterm clinical chorioamnionitis [54].…”