Pregnancy establishment depends on a pre-existent population of thymic-derived uterine Foxp3+ cells while pregnancy maintenance relies on de novo converted regulatory T cells (71.1)

Abstract

Abstract Pregnancy represents a challenge for the maternal immune system; it has to be alert against pathogens while tolerating paternal alloantigens in fetal structures. The maternal immune system is aware of these alloantigens, actively tolerating them to ensure the survival of the fetus. Regulatory T cells (Treg) are reportedly involved in allotolerance towards paternal antigens. In mouse models, the transfer of antigen-specific Treg can protect from immunological rejection of the fetuses. However, Treg generation and indispensability for pregnancy remained unclear. Treg accumulate during the receptive phase of the estrous cycle as documented by in vivo imaging using a 2-photon microscope. Treg depletion prior to and during very early pregnancy (foxp3.DTR mice) leads to impaired implantation, while their depletion at later time points does not interfere with gestation. Helios+ cells leave the thymus and accumulate in blood and uterus-draining lymph nodes during early pregnancy. At later stages, Foxp3+ Treg are generated de novo in the periphery as we demonstrated in a Rag-model of cell transfer. While naturally occurring Treg are needed for pregnancy establishment, their absence at later stages is compensated by the generation of Foxp3+ cells from Foxp3- cells. Our data provides new insights in the generation/ function of Treg during pregnancy, which is essential to understand natural mechanisms of tolerance acquisition.