Exploring the Origin and Antigenic Specificity of Maternal Regulatory T Cells in Pregnancy

Successful pregnancy outcome is partially determined by the suppression of reactive effector T cells by maternal regulatory T cells (T_Regs) at the maternal-fetal interface. While a large area of research has focused on the regulation of peripherally-induced T_Reg (pT_Reg) distribution and differentiation using transgenic mouse models and human samples, studies focusing on the role of T_Regs derived from the thymus (tT_Regs), and the potential role of central tolerance in maternal-fetal tolerance is less explored. The genome of the fetus is composed of both the tissue-specific and paternally-inherited antigens, and a break in maternal immune tolerance to either antigen may result in adverse pregnancy outcomes. Notably, "self"-antigens, including antigens that are highly restricted to the fetus and placenta, are promiscuously expressed by medullary thymic epithelial cells under the control of Autoimmune Regulator (Aire), which skews the tT_Reg T cell receptor (TCR) repertoire to be specific toward these antigens. T_Regs that circulate in mothers during pregnancy may be comprised of T_Regs that stem from the thymus as well as those induced in the periphery. Moreover, despite a wealth of research dedicated to elucidating the function of T_Regs in maternal-fetal tolerance, little is understood about the origin of these cells, and whether/how tT_Regs may contribute. Investigation into this question is complicated by the absence of reliable markers to distinguish between the two. In this review, we discuss how distinct types of fetal/placental antigens may determine the generation of different subtypes of T_Reg cells in the mother, and in turn how these may promote maternal tolerance to the fetus in pregnancy.