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.