Maternal T Regulatory Cell Depletion Impairs Embryo Implantation Which Can Be Corrected With Adoptive T Regulatory Cell Transfer

Abstract

Maternal immune tolerance of fetal engraftment is critical for the establishment and maintenance of pregnancy, but the exact mechanisms permitting this semi-allograft in the maternal host are not completely understood. Further, failure of the embryo to implant in the uterus accounts for at least 30% of the best prognosis in vitro fertilization cycles when a perfect embryo is transferred to a normal uterus. We hypothesized that T regulatory cells (T_regs), defined by CD4⁺CD25hi surface expression and the FoxP3+ transcription factor, play an important role in the initiation of the earliest stages of pregnancy, specifically implantation of the embryo. In this study, we evaluated the role of T_regs in the establishment of pregnancy using a conditional depletion of T_reg transgenic mouse model. We found that embryo implantation in the syngeneic mating was defective as evidenced by smaller litter sizes after T_reg depletion and that embryo implantation could be restored by adoptively transferring T_regs into the mating mice. In allogeneic mating, litter sizes were not different but breeding efficiency was significantly decreased. These data reveal that T_regs are important for the establishment of the earliest stages of pregnancy and may be a potential cause of infertility due to recurrent implantation failure, which may be amenable to cellular or pharmacologic therapy to improve maternal immune tolerance of embryo implantation.