Could Fetal Immune Reactions Spark Preterm Labor?

Original Paper: Alloreactive fetal T cells promote uterine contractility in preterm labor via TFN-α and IFN-γ

While pregnancy is often characterized as a period of excitement and anticipation, it also marks a time of uncertainty regarding the well-being of the baby. A standard, healthy pregnancy lasts about 40 weeks. However, for some women, labor begins prematurely, before the 37th week of pregnancy. Every year, about 15 million babies are born pre-term, and birth complications are the leading cause of death for children under the age of 5 [1]. Children who survive often face a lifetime of disability and impairment.Though the specific causes of preterm labor are unknown, researchers have found that infection and inflammation are amongst the most common causes of spontaneous preterm labor (PTL) [2]. Considering this, Frascoli et al. seek to understand if an inflammatory environment in mothers with PTL causes an increased activation of fetal immune cells. Typically, research on the maternal-fetal interface has focused on maternal cells tolerating the fetus. By focusing more on fetal cells, Frascoli et al. changed this: what if fetal immune cells are capable of recognizing and targeting maternal cells?

First, we must consider how the mother's womb allows the fetus to develop there for 9 months. Think about it... half of the fetus' genes are from the father, so half of the fetus is essentially foreign to the mother's body. Since this is the case, how does the mother's body know the fetus is not foreign, thereby preventing her immune system from targeting it? Basically, during pregnancy, the fetus is protected from an immune attack through a bunch of complex interactions at the fetal-maternal interface, as shown below: 

Figure 1. (Source: https://www.researchgate.net/figure/Multiple-mechanisms-underlie-maternal-tolerance-of-the-fetus-Mothers-via-changes-that_fig1_7879978)

In the current study conducted by the University of California, San Francisco, Frascoli et al. considered 89 patients with healthy pregnancies and 70 patients with spontaneous PTL. Considering the link between infection/inflammation and PTL, they first examined cytokines in both maternal and fetal cells. Cytokines are important to consider because they are often proinflammatory, which means that when activated, these small signaling molecules promote inflammation. The researchers found that preterm infants exhibit significantly elevated amounts of proinflammatory cytokines as compared to infants born at full-term. Interestingly, no significant differences in cytokine levels between patients with and without PTL. Many of the elevated cytokines are produced by activated dendritic cells- this is important because activated DCs are what interact with T and B cells to mount a sophisticated immune response. Because of this, Farscoli et al. considered whether fetal DCs are activated during PTL. They ultimately found higher levels of activated dendritic cells as well as higher levels of memory T cells in PTL infants as compared to full-term infants. This could indicate that the fetal immune system plays a role in inducing PTL.

Farscoli et al. also found that premature infant cord blood exhibited a higher prevalence of microchimerism. "Microchimerism" basically refers to the phenomena that one can carry a number of cells that originate from another individual (and are therefore genetically distinct from the cells of a host individual) (Figure 2). So in this case, premature infants possessed a higher level of maternal cells than did full-term infants. This led the researchers to hypothesize that higher levels of microchimerism result in the priming of fetal T cells to specifically target maternal antigens. That is, higher levels of microchimerism could prime fetal immune cells to mount an immune response against substances specific to the mother. 

Figure 2. (Source: https://www.omicsonline.org/emerging-questions-in-materno-fetal-microchimerism-2161-038X.S1-002.php?aid=2537) 

To test whether fetal T cells are specifically activated against maternal antigen, Farscoli et al. examined how maternal and fetal T cells interacted with each other as well as with a control. They found significant increases in fetal T cells against maternal antigens in PTL pregnancies as compared to full-term pregnancies. These increases were specific for maternal antigens, as they were not observed when preterm fetal T cells were stimulated with antigens from third-party controls. so, this supports the hypothesis that fetal immune cells could elicit an immune response specifically against maternal antigens. 

Lastly, Farscoli et al. utilized a mouse model to determine the effect of inflammatory cytokines (particularly TFN-α and IFN-γ) on fetal survival. Injection of these activated T cells resulted in increased fetal resorption, whereas transfer of non-activated T cells did not result in increased resorption. Also, increases in resorption appear dependent on TFN-α and IFN-γ, as the transfer of T cells from mice deficient in either cytokine failed to cause resorption. These results are significant in pinpointing TFN-α and IFN-γ as central cytokines in disrupting maternal-fetal tolerance.

Considering these results, Farscoli et al. sought to determine whether the hyperactive immune components of premature infants have a causal relationship with preterm birth. The researchers co-cultured T cells of a premature infant with maternal cells from the smooth muscle of the uterus. The results were striking: T-cells from premature children induced contraction of uterine cells whereas full-term infant T-cells exhibited no effect on uterine contraction. The results are shown in the figure below, where the fetal PTL was the only condition that caused contractions- the full-term fetal and conditions that lacked either TFN-α or IFN-γ did not cause contractions. Thus, TFN-α and IFN-γ must play a key role in inducing uterine contractions during PTL. 

Figure 3

From all of this, researchers concluded that preterm labor could occur when the mother has an infection, which would stimulate inflammatory cytokines like TFN-α and IFN-γ. This maternal immune response could unintentionally induce an immune response in the fetus, causing the fetus to release higher levels of inflammatory cytokines and activatory DCs, eventually leading to uterine contractions. Now that this pathway has been elucidated, the researchers can work towards developing new PTL treatment strategies that manipulate different aspects of this cascade.


References
[1] https://www.who.int/news-room/fact-sheets/detail/preterm-birth
[2] R. Romero, J. Espinoza, L. F. Gonçalves, J. P. Kusanovic, L. Friel, S. Hassan, The role of inflammation and infection in preterm birth. Semin. Reprod. Med. 25, 021–039 (2007).