Abstract
During successful pregnancy, a woman is immunologically tolerant of her genetically and antigenically disparate fetus, a state known as maternal-fetal tolerance. How this state is maintained has puzzled investigators for more than half a century. Diverse, immune and nonimmune mechanisms have been proposed; however, these mechanisms appear to be unrelated and to act independently. A population of immune suppressive cells called myeloid-derived suppressor cells (MDSCs) accumulates in pregnant mice and women. Given the profound immune suppressive function of MDSCs, it has been suggested that this cell population may facilitate successful pregnancy by contributing to maternal-fetal tolerance. We now report that myeloid cells with the characteristics of MDSCs not only accumulate in the circulation and uterus of female mice following mating but also suppress T cell activation and function in pregnant mice. Depletion of cells with the phenotype and function of MDSCs from gestation d 0.5 through d 7.5 resulted in implantation failure, increased T cell activation, and increased T cell infiltration into the uterus, whereas induction of MDSCs restored successful pregnancy and reduced T cell activation. MDSC-mediated suppression during pregnancy was accompanied by the down-regulation of L-selectin on naïve T cells and a reduced ability of naïve T cells to enter lymph nodes and become activated. Because MDSCs regulate many of the immune and nonimmune mechanisms previously attributed to maternal-fetal tolerance, MDSCs may be a unifying mechanism promoting maternal-fetal tolerance, and their induction may facilitate successful pregnancy in women who spontaneously abort or miscarry because of dysfunctional maternal-fetal tolerance.