Bidirectional regulation between 1st trimester HTR8/SVneo trophoblast cells and in vitro differentiated Th17/Treg cells suggest a fetal-maternal regulatory loop in human pregnancy

Abstract

Problem: During normal pregnancy, delicate crosstalk is established between fetus-derived trophoblasts and maternal immune cells to ensure maternal-fetal tolerance and successful placentation. Dysfunction in these interactions has been highly linked to certain pregnancy complications.

Method of study: Naïve CD4⁺ T cells were cultivated with or without 1st trimester derived trophoblast cell line HTR8/SVneo cells in the absence or presence of T helper 17 (Th17) or regulatory (Treg)cell-inducing differentiation conditions. After 5 days of co-culture, HTR8/SVneo cells and CD4⁺ T cells were harvested and analyzed using flow cytometry.

Results: CD4⁺ T cells exposed to HTR8/SVneo cells showed enhanced induction of CD4⁺ Foxp3⁺ Treg cells with strong expression of TGF-β1 and inhibitory molecules (cytotoxic T lymphocyte-associated protein-4 [CTLA-4], T-cell immunoglobulin mucin-3 [Tim-3], and programmed cell death-1 [PD-1]). Though not effecting Th17 differentiation, exposure to HTR8/SVneo cells promoted increased expression of proliferative and apoptotic markers on Th17 cells. Co-culture with Th0 cells, or differentiated Th17 or Treg cells, down-regulated Caspase-3 and MMP-9 (but not MMP-2) expression in HTR8/SVneo cells, while promoting Ki67 expression.

Conclusions: HTR8/SVneo cells regulated maternal CD4⁺ T-cell differentiation, resulting in the expansion of immunosuppressive Treg cells, while CD4⁺ T cells might promote the growth, and control the invasiveness of HTR8/SVneo cells. Thus, a bidirectional regulatory loop might exist between trophoblasts and maternal immune cell subsets, thereby promoting harmonious maternal-fetal crosstalk.

Keywords: HTR8/SVneo cells; Th17 cells; Treg cells; pregnancy; trophoblasts.