Evidence for a Selective Migration of Fetus-Specific CD4+CD25bright Regulatory T Cells from the Peripheral Blood to the Decidua in Human Pregnancy

Abstract

During pregnancy, the maternal immune system has to tolerate the persistence of fetal alloantigens. Many mechanisms contribute to the prevention of a destructive immune response mediated by maternal alloreactive lymphocytes directed against the allogeneic fetus. Murine studies suggest that CD4+CD25+ T cells provide mechanisms of specific immune tolerance to fetal alloantigens during pregnancy. Previous studies by our group demonstrate that a significantly higher percentage of activated T cells and CD4+CD25bright T cells are present in decidual tissue in comparison with maternal peripheral blood in human pregnancy. In this study, we examined the phenotypic and functional properties of CD4+CD25bright T cells derived from maternal peripheral blood and decidual tissue. Depletion of CD4+CD25bright T cells from maternal peripheral blood demonstrates regulation to third party umbilical cord blood cells comparable to nonpregnant controls, whereas the suppressive capacity to umbilical cord blood cells of her own child is absent. Furthermore, maternal peripheral blood shows a reduced percentage of CD4+CD25brightFOXP3+ and CD4+CD25brightHLA-DR+ cells compared with peripheral blood of nonpregnant controls. In contrast, decidual lymphocyte isolates contain high percentages of CD4+CD25bright T cells with a regulatory phenotype that is able to down-regulate fetus-specific and fetus-nonspecific immune responses. These data suggest a preferential recruitment of fetus-specific regulatory T cells from maternal peripheral blood to the fetal-maternal interface, where they may contribute to the local regulation of fetus-specific responses.

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

“…Interestingly, pregnant women displayed a lower proportion of cells expressing HLA-DR in the 0.5% CD4 + CD25 highest and the CD4 + cell population compared to controls, which is in line with a very recent report (45). We did not observe a decreased proportion of CD4 dim CD25 high cells showing the CD127 low phenotype, indicating that during pregnancy, Foxp3 is stable and still capable of suppressing CD127 expression.…”

“…We report that Tregs in pregnant women display reduced Foxp3 expression, a finding recently acknowledged also by Tilburgs and colleagues (45). Further, Tregs found in pregnant women seem more activated (increased CD45R0 + and reduced CD45RA + frequencies) compared with non-pregnant women.…”

T cell apoptosis at the maternal–fetal interface in early human pregnancy, involvement of galectin-1

“…Particular attention has been paid recently to the role of regulatory T cells in maternal-fetal tolerance (11,12). Interestingly, CD4 ϩ CD25 ϩ regulatory T cells have been shown to mediate their suppressive activity through gal1 (40).…”

“…Various mechanisms to suppress potentially alloreactive placental T cells and tolerize the maternal immune system toward the fetus have been proposed in mice and humans. These include placental expression of Fas and Fas ligand (6,7), T cell starvation through tryptophan depletion by indolamine 2,3-dioxygenase (8), ligation of the inhibitory ligand PD-L1 expressed on T cells in the gravid uterus (9), Th2 cytokine polarization (10), suppression by CD4 ϩ CD25 ϩ regulatory T cells (11,12), and progesterone-induced Th2-type responses (13). A number of redundant immunosuppressive systems exist at the maternal-fetal interface, not very surprisingly in a system so essential for species survival.…”

Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance

“…Adoptive transfer reconstitution of BALB/c nude mice with lymphocytes depleted of Tregs results in smaller litters from allogenic matings (9). Treg populations peak in peripheral blood lymphocytes during the second trimester of human pregnancies and accumulate in the decidua (10).…”