Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

Abstract

The mechanisms underlying immune tolerance during pregnancy are poorly understood. In this regard, Treg seem to play an important role in mediating maternal tolerance to the fetus. We proposed a crucial role of T regulatory cells (Treg) in avoiding immunological rejection of the fetus after observing diminished number and function of Treg in abortion-prone mice. We further confirmed the protective role of Treg during pregnancy by transferring pregnancy-induced Treg into abortion-prone mice, which prevented rejection. Here, we analyzed the mechanisms involved in Treg-mediated protection. As expected, Treg therapy prevented abortion, while expanding the peripheral and thymic Treg population. Surprisingly, the decidual levels of the Th1 cytokines IFN-c and TNF-a were not diminished after therapy. Interestingly, the mRNA levels of leukemia inhibitory factor, TGF-b and heme oxygenase-1 at the fetal-maternal interface were dramatically up-regulated after Treg transfer, while the levels of indolamine 2,3-dioxygenase remained unchanged. Our data suggest that Treg treatment can not prevent T cell infiltration or high Th1 levels but is able to create a privileged tolerant microenvironment at the fetal-maternal interface, further shedding light onto the molecular mechanisms involved in pregnancy tolerance.

Anti-apoptotic seminal vesicle protein IV inhibits cell-mediated immunity

“…In addition, the occurrence in uterus at blastocyst implanting time of a high number of protective molecules (Leukemia Inhibitory Factor, heme oxygenase HO-1, IL-10, TGF-, etc. ), tolerogenic CD4 + CD25 + Foxp3 + T Reg cells (Zenclussen et al, 2006), and mast cells (Dey et al, 2004), together with the recent finding in long-term allograft tolerance systems of a novel T Reg -IL-9-mast cell immunosuppressive relationship [T Reg (TGF-)  IL-9  mast cell  (TGF-)] (Lu et al, 2006;Zenclussen et al, 2006;), is of substantial help for the formation of an immunotolerant and antiapoptotic implantation site. The presence of SV-IV in the uterus at this location following insemination could also contribute to the definition of the immunotolerant characteristics of the site, although the evidence that the protein is present in this location at the implantation time is only circumstantial (SV-IV is present in rat ejaculated semen in free and sperm-bound form; an SV-IV immunorelated protein has been found in rat uterine lysates and in human seminal plasma) (Ostrowski et al, 1979;Paonessa et al, 1984;Abrescia et al, 1985;Metafora et al, 1987a;Metafora et al, 1987b and unpublished results from our lab; Manco et al, 1988).…”

Systemic reduction of functionally suppressive CD4dimCD25highFoxp3+ Tregs in human second trimester pregnancy is induced by progesterone and 17β-estradiol

“…In a murine abortion model, Tregs adoptively transferred from normal pregnant mice induce a fetal-protective microenvironment and provide protection against aggressive anti-fetal immune reactions (14,15). The cause of the Treg-protective mechanisms and Treg expansion seen during murine pregnancy has been ascribed pregnancy hormones (13), foremost estrogens (16), but also fetal alloantigens (14,17).…”

To the Editor

“…Having for a long time been researching pregnancy-induced 'tolerance', and especially the involvement of T cells in this process, I have read with interest the paper published in your journal by the Ana Claudia Zenclussen group [1].…”

“…2A in [11] whereas only 2% IL-10 + cells were noted (Fig. 5A) for CBA/J Â BALB/c matings in [1], despite identical experimental conditions.…”