Fetal Intervention Increases Maternal T Cell Awareness of the Foreign Conceptus and Can Lead to Immune-Mediated Fetal Demise

Abstract

Fetal interventions to diagnose and treat congenital anomalies are growing in popularity but often lead to preterm labor. The possible contribution of the maternal adaptive immune system to post-surgical pregnancy complications has not been explored. We recently showed that fetal intervention in mice increases maternal T cell trafficking into the fetus and hypothesized that this process may also lead to increased maternal T cell recognition of the foreign conceptus and subsequent breakdown in maternal-fetal tolerance. Here, we show that fetal intervention in mice results in accumulation of maternal T cells in the uterus and that these activated cells can produce effector cytokines. In adoptive transfer experiments, maternal T cells specific for a fetal alloantigen proliferate after fetal intervention, escape apoptosis, and become enriched compared to endogenous T cells in the uterus and uterine-draining lymph nodes. Finally, we demonstrate that such activation and accumulation can have a functional consequence: in utero transplantation of hematopoietic cells carrying the fetal alloantigen leads to enhanced demise of semiallogeneic fetuses within a litter. We further show that maternal T cells are necessary for this phenomenon. These results suggest that fetal intervention enhances maternal T cell recognition of the fetus and that T cell activation may be a culprit in post-surgical pregnancy complications. Our results have clinical implications for understanding and preventing complications associated with fetal surgery such as preterm labor.

Preterm labor: One syndrome, many causes

“…, CXCL-10) ( 47 ) has been observed in chronic chorioamnionitis. Breakdown of maternal-fetal tolerance may be particularly relevant to preterm labor occurring after fetal surgery or stem cell transplantation - interventions in which there is an increase in the number of maternal T-cells in the fetal circulation ( 48 ). The mechanisms linking disorders in tolerance and spontaneous preterm labor remain to be defined.…”

Maternal–fetal cellular trafficking

“…Alterations in post-surgical levels chimerism may be due to fetal cytokine production leading to changes in trans-placental cellular trafficking, or proliferation of maternal cells already present in the fetal circulation. We have shown that maternal T cells can cause demise of allogeneic fetuses after fetal intervention, suggesting a pathogenic role for such alterations in trafficking in this context [47]. Understanding the effects of fetal intervention on cellular trafficking, and whether these changes are causative in the onset of pregnancy complications may help identify new treatment strategies.…”

Increased maternal T cell microchimerism in the allogeneic fetus during LPS-induced preterm labor in mice

“…One weakness in our study is that we could not determine whether increased MMc is secondary to increased trafficking or secondary to increased proliferation of cells after entering the fetal circulation. Although we previously showed that adoptively transferred antigen-specific maternal T cells proliferate at the maternal-fetal interface, 21 there is an overall low level of trafficking in the fetus that precludes more detailed analysis of these cells. Our study also does not address whether maternal T cells contribute to the onset of preterm labor or whether they simply proliferate in the inflammatory environment induced by LPS.…”

“…These results are consistent with our recent report that maternal T cells mediate resorption in a fetal intervention model. 21 Further studies are required to determine whether enhanced microchimerism has a functional role in the onset of LPS-induced preterm labor.…”

“…20 Moreover, maternal T cells play a role in the selective demise of fetuses after fetal stem cell transplantation in mice. 21 We have also observed that patients undergoing fetal surgery have increased levels of maternal cells in fetal blood. 19 However, trafficking in a model of PTL that more closely resembles human inflammation-induced PTL has not been reported.…”