Systemic Increase in the Ratio between Foxp3+ and IL-17-Producing CD4+ T Cells in Healthy Pregnancy but Not in Preeclampsia

Abstract

Preeclampsia is the leading cause of morbidity and mortality in pregnancy. Although the etiology of preeclampsia is still unclear, it is believed to involve rejection of the fetus, possibly due to an imbalance between regulatory (Treg) and effector T cells. To test this, we compared the frequencies of circulating CD4+ T cells expressing Foxp3, IFN-γ, IL-10, or IL-17 at the end of the third trimester of healthy and preeclamptic pregnancies. The size of the Treg cell compartment, defined by the frequency of CD4+CD25high, CD4+CD127lowCD25+, and CD4+Foxp3+ cells was significantly higher in normal compared with preeclamptic pregnancies. CD4+CD25high and CD4+CD127lowCD25+ populations in preeclampsia were not significantly different from those in nonpregnant controls, whereas CD4+Foxp3+ cells numbersre slightly lower in preeclampsia. The suppressive activity of ex vivo-sorted CD4+CD127lowCD25+ Treg cells was not significantly different between the three study groups. The percentage of CD4+IL-17-producing T cells decreased significantly in healthy compared with preeclamptic pregnancies and nonpregnant controls, whereas CD4+IL-10- and CD4+IFN-γ-producing cells remained unchanged. Consequently, the ratio of Foxp3+ Treg to IL-17-expressing CD4+ T cells was significantly increased in healthy but not in preeclamptic pregnancies. Thus, preeclampsia is associated with the absence of normal systemic skewing away from IL-17 production toward Foxp3+ expression. Finally, preeclamptic women had significantly higher levels of soluble endoglin, an inhibitor of TGF-β receptor signaling, which may bias toward IL-17 production. These results suggest that homeostasis between regulatory and proinflammatory CD4+ T cells might be pivotal for the semiallogeneic fetus to be tolerated within the maternal environment.

REVIEW ARTICLE: Th1/Th2/Th17 and Regulatory T‐Cell Paradigm in Pregnancy

“…31,32 In our study, the frequency of Th17 cells to CD4 + T cells during all stages of pregnancy period was similar to that in non-pregnant women, 32 but Santner-Nanan et al 33 reported that the frequency of Th17 cells in the third trimester of pregnancy was significantly lower compared to that of non-pregnant women. Further studies are needed to determine circulating Th17 cell levels during pregnancy.…”

“…34 Previous studies demonstrate that elevation of IL-17 is observed in acute renal rejection, 35 suggesting that increased Th17 cells in pregnancy decidua might be disadvantageous for the maintenance of pregnancy. 33 Unexpectedly, the frequency of Th17 cells in the decidua is significantly higher compared to that in peripheral blood. The uterine cavity is not completely sterile, and therefore, Th17 cells might play a role to induce protective immune response against extracellular microbes.…”

“…In contrast, a decreased population of Treg cells and an increased population of Th17 cells compared to non-pregnancy levels in preeclampsia have been reported. 33 Preeclampsia is associated with exaggerated systemic inflammatory changes 58 and poor angiogenesis because of increased levels of soluble Flt-1 and soluble endoglin 59 ( Fig. 3).…”

A case of psoriasis accompanied by arthritis after delivery

“…In addition, during pregnancy, Th1-type immunity is well controlled to avoid its overstimulation, probably due to the suppression by Treg, which are observed to increase in decidua (11). Furthermore, the level of IL-17 in normal pregnancy is lower than that in non-pregnancy, and Th17 is thought to be inhibited in the former condition (12). Taken together, in pregnancy, Th2/Treg-type immunity should be predominant over Th1/Th17-type immunity by the above changes in the hormones and cytokines, and the subsequent rebound of Th1/Th17 may occur after delivery.…”

Association between lower frequency of R381Q variant (rs11209026) in IL-23 receptor gene and increased risk of recurrent spontaneous abortion (RSA)

“…In normal pregnancy, T reg cells prevent generation of an immune response against fetal tissue and a decrease in the number of T reg cells is associated with abortion (Saito et al, 2005). In contrast, T H 17 cells promote inflammation and increased levels of T H 17 cells -accompanied by a decrease in T reg cell levels -were reported to occur in association with unexplained RSA events (Santner-Nanan et al, 2009).…”