Term and preterm labor: decreased suppressive activity and changes in composition of the regulatory T‐cell pool

Abstract

Regulatory T cells (Tregs) exert a key role in tolerance induction to the semi-allogeneic fetus. Currently, it is not known whether immunological rejection processes are involved in the induction of normal term or irresistible preterm labor. In this study, we examined whether there were differences in the percentage of the total CD4 þ CD127 low þ / À CD25 þ FoxP3 þ -Treg-cell pool, its suppressive activity and its composition with distinct Treg subsets (HLA-DR low þ -, HLA-DR high þ -, HLA-DR À -and naive CD45RA þ -Tregs) between preterm and term laboring women. We found that its percentage was decreased neither in term nor in preterm laboring women. Its suppressive activity was strongly diminished in preterm laboring women and to a lesser extent in spontaneously term laboring women. During the normal course of pregnancy, its composition changed in such a way that the percentage of naive CD45RA þ -Tregs increased while the percentage of the highly suppressive HLA-DR low þ -and HLA-DR high þ -Tregs decreased significantly until term. With the onset of spontaneous term labor this phenomenon was reversed and reached significant values postpartum. In addition, we confirmed that both the decreased percentage of HLA-DR þ -Tregs within the total Treg-cell pool and their decreased level of HLA-DR expression (depending on the percentage of HLA-DR low þ -and HLA-DR high þ -Tregs) had a reducing effect on the suppressive activity of the total Treg cell pool in preterm laboring women. However, spontaneous term delivery was associated with increasing percentages of HLA-DR þ -Tregs and increasing HLA-DR expression of this Treg subset. Therefore, it becomes apparent that the mechanisms inducing term or preterm labor may be completely different. Keywords: pregnancy; preterm labor; regulatory T cells; subsets of regulatory T cells; term labor; tolerance induction During pregnancy, the maternal immune system is continuously confronted with paternal alloantigens, which are expressed by the fetus and the placenta. The complex immunologically controlled mechanisms that prevent the rejection of the fetus are still incompletely understood. Normally, the fetus grows and develops very well with ongoing pregnancy, until the onset of spontaneous labor induces vaginal delivery of the fetus after about 38-42 weeks of gestation. Unfortunately, in about 12-13% cases in the United States and 5-9% cases in many other developed countries, pregnancy ends as a premature birth, 1 often because of the occurrence of contractions that cannot be inhibited by tocolytic treatment. Currently, it is not known whether the maternal immune system rejects the semiallogeneic fetus at term, nor do we know whether immunological rejection processes participate in the induction of irresistible preterm labor. However, studies in mouse models clearly demonstrated that immunosuppressive regulatory T cells (Tregs) are decisively involved in inducing maternal immune tolerance to the fetus. 2 Maternal CD4 þ CD25 high þ -Tregs were shown to be expanded in both allogeneic ...

Membrane progesterone receptors in human regulatory T cells: a reality in pregnancy

“…5 When comparing our results with those published in the literature, this population remained almost unchanged throughout the whole pregnancy, with a slight increase on delivery day, which contrasts with published literature. CD4 + CD25 high CD127 low isolated Treg cells appear to be the best Treg population achieved regarding purity, function, stability and in vitro expansion capacity, promising isolation of pure Treg populations with high suppressive activity.…”

“…27 The data reported in the literature concerning the effect of pregnancy-specific hormones on FoxP3 expression by Treg cells are very contradictory. 5 The withdrawal of hormones at the end of pregnancy may affect FoxP3 expression by Treg cells, which was shown to be enhanced by progesterone in human studies. 3 Other authors postulate that progesterone, whose maximum levels are seen at the end of pregnancy, has the capacity to reduce FoxP3 expression by Treg cells in vitro.…”

“…25 Moreover, recent data indicate a significant decrease of Treg cells expressing FoxP3 in the 3rd trimester and women in labour at term. 5 We therefore also determined FoxP3 expression in our research, making some comparisons feasible. Within CD4 + CD25…”

“…3,4 However, it is not known whether the Treg suppressive mechanism is specific to PTB or if it is also involved in spontaneous normal term birth. 5 Progesterone has a major role in pregnancy maintenance and its secretion has been demonstrated in the amnion, chorion and decidua in humans. 6,7 In the 1st trimester, progesterone is critical to pregnancy preservation until the placenta takes over this function.…”

Immunological determinants of implantation success

“…Interestingly this decline is most evident in HLA-DR + Treg cells, which are those with the highest suppressive capacity. A reduction in Treg cells may be required to halt immune tolerance as one of the triggers for parturition (Schober et al, 2012. Placental trophoblasts, which constitutively secrete high levels of TGFB, likely exert direct effects on Treg cells with co-culture experiments showing that they induce naïve T cells into Foxp3 expressing cells with a Treg cell-like cytokine profile (Ramhorst et al, 2012).…”