Abstract
Semi-allogenic fetuses are not rejected by the maternal immune system because feto-maternal tolerance induced by CD4+CD25+FoxP3+ regulatory T (Treg) cells is established during pregnancy. Paternal antigen-specific Treg cells accumulate during pregnancy, and seminal plasma priming plays an important role in expanding paternal antigen-specific Treg cells in mouse models. Although paternal-antigen specific Treg cells have not been identified in humans, recent studies suggest that antigen-specific Treg cells exist and expand at the feto-maternal interface in humans. Studies have also revealed that reduction of decidual functional Treg cells occurs during miscarriage with normal fetal chromosomal content, whereas insufficient clonal expansion of decidual Treg cells is observed in preeclampsia. In this review, we will discuss the recent advances in the investigation of mechanisms underlying Treg cell-dependent maintenance of feto-maternal tolerance.
Highlights
Feto-maternal tolerance protects the fetal tissues from rejection and leads to a successful pregnancy [1,2,3,4,5,6,7]
After implantation of the blastocyst in the uterine endometrium, trophoblasts start to invade the endometrial tissue, and uterine spiral artery. Maternal lymphocytes such as CD4+ T cells, CD8+ T cells, and CD16−CD56bright natural killer (NK) cells express activation markers on their surfaces, suggesting that maternal lymphocytes recognize trophoblasts or fetuses [8]
Our study reported for the first time that clonal expansion of decidual Treg cells was impaired in preeclampsia, suggesting that paternal antigen-specific tolerance might be insufficient
Summary
Feto-maternal tolerance protects the fetal tissues from rejection and leads to a successful pregnancy [1,2,3,4,5,6,7]. Maternal Tim3+PD-1+CD8+ T cells recognize PD-L I expressed on EVTs, resulting in trophoblast antigen-specific tolerance [52]. This subset shows a lower expression of perforin and granzyme B [53] These reports suggest that antigen-specific CTLs exist at the feto-maternal interface, but their cytotoxic activity is controlled by the placental tissue [53]. Previous studies suggest that Treg cells play an essential role in the induction of paternal antigen-specific tolerance in allogenic pregnancy in mice. The local fetal antigen-specific Treg cells might be expanded at the draining lymph nodes by seminal plasma-priming and migrate to the uterus after pregnancy. Decidual Treg cells, but not peripheral blood Treg cells, showed higher suppression toward self-fetal cord blood than 3rd party cord blood, suggesting that fetal antigen-specific Treg cells might exist at the feto-maternal interface during human pregnancy [56].
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