T regulatory cells: regulating both term and preterm labor?

Pregnancy is a beautiful example of immunological regulation, where several changes occur in the immune system of the mother that allow her to tolerate the fetus, a semi-allogenic graft. Immune regulation during pregnancy is promoted by several factors. One of them is the T-cell subset with immunomodulatory properties, regulatory T cells (Tregs; CD4+CD25+FoxP3+). In this issue of Immunology and Cell Biology, Schober et al. demonstrate that different Treg subsets are present in term and preterm labor (PTL). The role of Tregs during the gestational period has been studied in both mice and human pregnancy. In placental mammals, the development of peripheral Tregs is crucial for mediating tolerance towards the paternal antigens of the fetus at the maternal–fetal interface. From a clinical perspective, it was recently shown that alterations in the proportion of Tregs were documented in patients with preeclampsia (PE) and it was believed that this could be contributing to the pathogenesis of this syndrome.3 Later on, the same group demonstrated that throughout pregnancy four distinct subsets of Tregs (defined as CD4+CD127low+/−CD25+FoxP3+) could be identified on the basis of expression of CD45RA and the major histocompatibility molecule HLA-DR, namely: DRhigh+ CD45RA−, DRlow+ CD45RA−, DR− CD45RA− and naive DR− CD45RA+ Tregs. Interestingly, the proportion of every subset seems to be relevant in the physiopathology of pregnancy complications, such as PE and PTL. Women who developed these pathologies have a reduced proportion of naive DR−CD45RA+ Tregs within their total Treg pool. In addition, preeclamptic women showed high proportions of DRhigh+CD45RA− Tregs and DRlow+CD45RA− Tregs, while in PTL women showed high proportions of DR−CD45RA− and DRlow+ CD45RA− Tregs. In PTL women, the suppressive activity of Tregs was strongly reduced and this correlated with a reduced level of HLA-DR expression (that is, MFI) on DR+ Tregs. Interestingly, it has also been demonstrated that the participation of Tregs in pregnancy is regulated by hormones, especially by progesterone, and that the expression of HLA-DR and the low expression of CD127 correlate with the suppressive functions of these cells.