Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice

Abstract

Maternal T cells acquire a transient state of tolerance specific for paternal alloantigens during pregnancy. CD4(+)CD25(+) regulatory T (Treg) cells play a central role in induction and maintenance of tolerance. We have studied the role of Treg cells for the maintenance of allogeneic pregnancy during the implantation period, early pregnancy period and late pregnancy period. We performed depletion of Treg cells using treatment with anti-CD25 monoclonal antibody (mAb) in allogeneic or syngeneic pregnant mice. BALB/c or C57BL/6 female mice were mated with BALB/c or C57BL/6 male mice, and anti-CD25 mAb was injected intraperitoneally on day 2.5 post-coitum (pc), or days 4.5 and 7.5 pc, or days 10.5 and 13.5 pc. Administration of 0.5mg of anti-CD25 mAb induced depletion of CD4(+)CD25(+)Foxp3(+) Treg cells in both allogeneic and syngeneic pregnancy. The extent of depletion of CD4(+)CD25(+) Treg cells in spleen cells was 82.7%. This mAb treatment on day 2.5 pc of pregnancy induced implantation failure in allogeneic pregnant mice, but not in syngeneic pregnant mice. In addition, anti-CD25 mAb treatment on days 4.5 and 7.5 pc significantly increased resorption rates in allogeneic pregnant mice, but not in syngeneic pregnant mice. Interestingly, anti-CD25mAb treatment on days 10.5 and 13.5 pc reduced Treg cell numbers, but this treatment did not induce any abnormal pregnancy parameters such as intrauterine growth restriction, hypertension, or proteinuria. These findings suggest that CD4(+)CD25(+)Foxp3(+) Treg cells are important to mediate maternal tolerance to the allogeneic fetus in the implantation phase and early stage of pregnancy, but Treg cells might not be necessary for maintenance of the late stage of allogeneic pregnancy.