Myeloid-derived suppressor cells contribute to maintaining allogeneic pregnancies (IRC4P.461)

Abstract In pregnant women the fetus is an allograft and successful human pregnancies require maternal tolerance to fetal alloantigens. Myeloid-derived suppressor cells (MDSC) are potent inducers of T cell tolerance in tumor-bearing hosts. MDSC levels also increase during normal pregnancy; however, whether they mediate maternal tolerance is unknown. To investigate if MDSC are involved, female BALB/c (H-2d) mice were caged overnight with allogeneic C57BL/6 (H-2b) males. The following morning, females with vaginal plugs indicative of copulation, were started on an MDSC depletion regimen. MDSC-depleted mice produced no offspring, while 46% of control-treated mice had healthy litters. One of the mechanisms MDSC use to inhibit anti-tumor immunity is to down-regulate CD62L (L-selectin) on T cells and prevent T cell entry into lymph nodes and subsequent activation. To determine if a similar mechanism is operative during pregnancy, mice were treated with granulocyte colony stimulating factor (G-CSF), an inducer of MDSC. G-CSF-treated, but not control-treated, mice contained elevated levels of MDSC, and elevated levels of naïve, circulating T cells with reduced expression of CD62L. MDSC-depletion of G-CSF-treated mice restored CD62L expression. These results suggest that MDSC promote maternal-fetal tolerance, and that tolerance during successful pregnancies may be due to the failure of T cells to enter lymph nodes where they could become activated to fetal alloantigens.