PD-1 but not CTLA-4 blockage abrogates the protective effect of regulatory T cells in a pregnancy murine model.

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 x BALB/c) on day 14 were adoptively transferred into abortion-prone mice (AP; CBA/J x DBA/2J) intravenously on day 2 of pregnancy. An amount of 250 microg 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 x DBA/2J murine model.