The recruitment of these ‘naïve’ CD4+ CD25− Foxp3+ cells was favored in a state of thymic involution or transient lymphopenia.34,38 In line with these results, a similar model of conversion of decidual CD4+ CD25− Foxp3+ into CD4+ CD25+ Foxp3+ Treg cells could be proposed because thymic involution is a constitutive event in humans and is known to be enhanced during murine pregnancy. Thus, we could suggest that in human normal pregnancy, the decidua might be a site where conversion of CD4+ CD25− Foxp3+ into CD4+ CD25+ Foxp3+ Treg cells takes place to compensate for the loss of functional thymus because of thymic involution. Contrasting to this hypothesis selleck products is a scenario concerning
Treg cells in murine pregnancy described by Zenclussen,11 who proposed that
fetal antigens pass through the maternal thymic medulla that is spared from involution and a systemic generation of pregnancy-specific Treg cells occurs. Taking in mind these suggestions, we could speculate that the enrichment of CD4+ CD25− Foxp3+ T cells in human first trimester decidua might be important for two purposes both beneficial to implantation and pregnancy: (i) to be a reservoir of ‘inactive’/‘naïve’ CD4+ CD25− Foxp3+ Treg cells that can rapidly be converted to ‘classical’ CD4+ CD25+ Foxp3+ Treg cell pool in decidua and GDC0449 (ii) to attenuate the CD4+ T effector cell activation by transient acquisition of the Foxp3 transcriptional factor thus shutting off the immune response. The similar levels of Foxp3 mRNA expression in the CD4+ CD25− and the CD4+ CD25+ cells that we found argue in favor for the first suggestion. How Rebamipide the Treg cells are recruited to the fetal–maternal interface in humans and their specificity is still open
questions. Aluvihare et al.26 showed that the systemic expansion of murine Treg cells was independent of fetal alloantigens and suggested that Treg cell recruitment and expansion are hormonally driven. In contrast, it was suggested that the presence of conceptus alloantigens potentiates the increase of Treg cell numbers and is associated with specific suppression of the maternal response against paternal alloantigens.47 Zenclussen et al.31 found that the adoptive transfer of CD4+ CD25+ Treg cells from normal pregnant but not from non-pregnant CBA/J mice completely prevented spontaneous abortion in the abortion-prone DBA/CBA murine model, suggesting that only Treg cells previously exposed to paternal alloantigens have protective regulatory activity in vivo. Thus, the causes of murine Treg expansion and their pregnancy-protective mechanisms have been ascribed to pregnancy hormones26 but also to fetal alloantigens.31,47 A hormonal Treg regulation in pregnancy and a specific downregulation of responses against paternal alloantigens has also been reported in humans.22,48 However, more studies are needed to confirm these results and elucidate the role of Treg cells locally and systemically.