Research ArticleFETAL IMMUNITY

Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γ and TNF-α

See allHide authors and affiliations

Science Translational Medicine  25 Apr 2018:
Vol. 10, Issue 438, eaan2263
DOI: 10.1126/scitranslmed.aan2263

Feisty fetal T cells can rebel in utero

Typically, when the fetal-maternal interface is examined, most of the focus is on the maternal cells tolerating the fetus. However, although the adaptive immune system of the fetus is not fully mature, fetal T cells exist and may recognize maternal cells. Frascoli et al. compared cord blood samples from pregnancies that ended in spontaneous preterm labor to those that were full term. They saw an increase in inflammatory cytokines and TH1 central memory fetal T cells in the preterm labor cases, as well as stronger reactions to maternal antigens. Experiments in vitro and in a mouse model suggested that production of TNF-α and IFN-γ by these fetal T cells may actually instigate preterm labor. Their results show that fetal T cells cannot be assumed to be inert and, perhaps, can influence the health of the pregnancy.


Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells. Moreover, preterm cord blood is characterized by the presence of a population of central memory cells with a type 1 T helper phenotype, which is absent in term infants, and an increase in maternal microchimerism. T cells from preterm infants mount a robust proliferative, proinflammatory response to maternal antigens compared to term infants yet fail to respond to third-party antigens. Furthermore, we show that T cells from preterm infants stimulate uterine myometrial contractility through interferon-γ and tumor necrosis factor–α. In parallel, we found that adoptive transfer of activated T cells directly into mouse fetuses resulted in pregnancy loss. Our findings indicate that fetal inflammation and rejection of maternal antigens can contribute to the signaling cascade that promotes uterine contractility and that aberrant fetal immune responses should be considered in the pathogenesis of PTL.

View Full Text

Stay Connected to Science Translational Medicine