Impact of regulatory T cell therapy on immune cell composition and fetal survival rate in abortion prone mice.

Abstract

Implantation of fertilised eggs and survival of a semi-allogenic embryo rely on the interactions between the cells and molecules preparing the uterus. We investigated the effect of regulatory T cell (Treg) therapy on the mechanism of local immune tolerance of mice prone to spontaneous abortion. Naive T cells were stimulated in vitro with 17β-oestradiol (E2), progesterone (P4) and TGF-β1 for 96h to generate induced Tregs (iTreg). The iTregs were injected into DBA/2-mated pregnant CBA/J female mice (abortion prone model). On day 14 of pregnancy, mice were killed and decidual and placental tissues were collected for cellular composition analysis. Abortion prone mice (PBS treated) showed significantly lower survival rates (P<0.0001), increased CD3+CD8+ (P<0.05), lower IDO+ (P<0.05) and increased natural killer cells (uNK) cell numbers (P<0.001) in the uterus, as well increased NK cells in the placenta (P<0.05) than in normal pregnant mice (CBA/J×BALB/c). Adoptive transfer of iTregs increased fetal survival in abortion-prone mice (P<0.01) and histopathological evaluation revealed a significantly decreased number of uNK cells in the uterus of TGF-β1-, E2- and P4-iTregs (P<0.05, P<0.0001 and P<0.05, respectively) than in the PBS treated group. In the placenta, we found significantly lower numbers of uNK cells from TGF-β1-, E2- and P4-iTregs than in the PBS treated group (P<0.05, P<0.05 and P<0.01, respectively). We propose that modulation of uterine NK cell activity through immunotherapy using Treg cells should be given more attention as an immunological strategy in the treatment of recurrent miscarriage.