Early Pregnancy Factor Enhances the Generation and Function of CD4⁺CD25⁺ Regulatory T Cells

Abstract

The mechanisms of fetal semi-allograft acceptance by the mother's immune system have been the target of many immunological studies. Early pregnancy factor (EPF) is a molecule present in the serum of pregnant mammals soon after conception that has been reported to have immunomodulatory effects. In the present study, we aimed to determine whether immune cells such as CD4 + CD25 + regulatory T cells (Tregs) are involved in the suppressive mechanism of EPF. Accordingly, CD4 + CD25 -T cells were isolated from spleens of female C57BL/6 mice and stimulated with anti-CD3 antibody, anti-CD28 antibody and IL-2 in the presence or absence of EPF. Flow cytometry was used to analyze the differentiation of CD4 + CD25 -T cells to CD4 + CD25 + Tregs. We thus found a remarkable rise in the Treg ratio in the EPF-treated cells. Higher mRNA and protein levels of fork head box P3 (Foxp3), a marker of the Treg lineage, were also observed in cells treated with EPF. Furthermore, the effect of EPF on Treg immunosuppressive capacity was evaluated. EPF treatment induced the expression of interleukin-10 and transforming growth factor β1 in Tregs. The suppressive capacity of Tregs was further measured by their capability to inhibit T cell receptor-mediated proliferation of CD4 + CD25 -T cells. We thus found that EPF exposure can enhance the immunosuppressive functions of Tregs. Overall, our data suggest that EPF induces the differentiation of Tregs and increases their immunosuppressive activities, which might be an important mechanism to inhibit immune responses during pregnancy.

Promoting Roles of Embryonic Signals in Embryo Implantation and Placentation in Cooperation with Endocrine and Immune Systems

“…Early pregnancy factors that inhibit T-cell-induced rosette formation were reported to be detected just after fertilization [111]. Later, several substances, such as platelet activating factor, thioredoxin, and chaperonin 10, were proposed as early pregnancy factors [112][113][114]. It was also reported that the embryo-derived pre-implantation factor (PIF), a novel embryo-specific 18-kDa peptide that is specifically expressed on the fetus and placenta [115], was secreted at the two-cell stage and was able to be detected in the maternal sera prior to implantation [116].…”

Symposium review: Immunological detection of the bovine conceptus during early pregnancy

“…For almost 2 decades, the nature of the factor mediating this response eluded investigators, but it was finally determined to share homology with chaperonin 10, a member of the heat shock/chaperonin protein family that participates in protein folding and stabilization in a wide array of cellular contexts (Cavanagh, 1996;Morton, 1998). Chaperonin 10 (also known as HSP10 and HSPE1) is expressed in a wide array of cell types and has been shown to modulate immune cell function, for example, by inducing formation of Treg cells and production of IL10 and TGFB (Chen et al, 2016). The role that HSP10 plays in ruminant pregnancy is yet unclear.…”

Characterization of the Highly Prevalent Regulatory CD24hiCD38hi B-Cell Population in Human Cord Blood

“…Maternal–fetal tolerance is achieved through different mechanisms such as an increase of Treg cells, expression of CD274 (PD-L1) in the trophoblastic tissue, and an increase of Breg cells (21, 22). Early pregnancy factor enhances Treg-cell production and IL-10 and TGF-β expression in splenocytes from female mice (23). In pregnant mice, the increase in Breg is necessary to avoid immunological abortion.…”