Reconsideration of the Role of Regulatory T Cells during Pregnancy: Differential Characteristics of Regulatory T Cells between the Maternal-Fetal Interface and Peripheral Sites and between Early and Late Pregnancy

Regulatory T (Treg) cells play an important role in implantation of the embryo and maintenance of pregnancy after allogeneic mating. Implantation failure, miscarriage, and preeclampsia are associated with decreased numbers of Treg cells or with dysfunctional Treg cells. Treg cells are classified into naturally occurring Treg (nTreg) cells or thymus-derived Treg (tTreg) cells that differentiate in the thymus and induce tolerance to self-antigens, while induced Treg (iTreg) or peripheral Treg (pTreg) cells differentiate in the periphery and induce transient tolerance to foreign antigens. Memory nTreg or iTreg cells were recently reported to accumulate in the uterus during early pregnancy and contribute to the establishment of pregnancy. Miscarriage is characterized by the downregulation of the total numbers of Treg cells rather than a downregulation of the numbers of paternal/fetal antigen-specific Treg cells. In addition to the volume of paternal/fetal antigen-specific CD8⁺ T cells, the number of paternal/fetal antigen-specific Treg cells, which protect the fetus/placenta against maternal immune cell attack, increases after the second trimester of pregnancy. Clonal Treg cells which are surrogate markers of paternal/fetal antigen-specific Treg cells in humans may be involved in the development of preeclampsia during the mid- to late pregnancy stage, as evidenced by their downregulation in the decidua of preeclamptic cases. This review summarizes recent findings on Treg cells and discusses the roles, in the maintenance of pregnancy, of different types of Treg cells such as paternal/fetal antigen-specific Treg, pregnancy-associated memory Treg, nTreg (or tTreg), and iTreg (or pTreg cells).