ORIGINAL ARTICLE: PD‐1 but not CTLA‐4 Blockage Abrogates the Protective Effect of Regulatory T Cells in a Pregnancy Murine Model

Abstract

Problem Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect paternal/fetal antigens from rejection by maternal effector cells. Accordingly, the transfer of Treg obtained from BALB/c‐mated CBA/J females prevents abortion in DBA/2J‐mated animals. The actual mechanism through which Treg mediate their protective effect is still inconclusive. Cytotoxic T lymphocyte antigen‐4 (CTLA‐4) and Programmed cell death 1 (PD‐1) are some of known Treg‐associated molecules; however, their role in Treg‐mediated fetal protection in murine model has not been investigated.Method of study Treg obtained from normal pregnant animals (NP; CBA/J × BALB/c) on day 14 were adoptively transferred into abortion‐prone mice (AP; CBA/J × DBA/2J) intravenously on day 2 of pregnancy. An amount of 250 μg of either anti‐PD‐1 or anti‐CTLA‐4 mAb were injected intraperitoneally on days 0, 3, 6 and 9 of pregnancy. Controls received Treg + IgG or Treg + PBS. NP or AP treated with PBS served as additional controls.Results Blocking PD‐1 abrogated the protective effect of Treg, resulting in a higher median abortion rate in comparison with the Treg/isotype‐treated control while CTLA‐4 blockage did not interfere with the protective effect of Treg. This was associated with a diminished number of vascular endothelial growth factor‐A+ cells, previously reported as stimulators of lymphocyte extravasation in preterm labor.Conclusion Our data suggest PD‐1 as an important mediator in Treg‐induced fetal protection in the CBA/J × DBA/2J murine model.