Abstract Survival of the allogenic pregnancy depends on the maintenance of immune tolerance to paternal alloantigen at the feto-maternal interface. Multiple localized mechanisms contribute to fetal evasion from the mother’s immune rejection as fetus is exposed to a wide range of stimulatory substances such as maternal allo-antigens, microbes and amniotic fluids. Here, we demonstrate that CD71+ erythroid cells are expanded at the feto-maternal interface and in the periphery during pregnancy. These cells exhibit immunosuppressive property and their abundance is associated with a Th2 skewed immune response, as their depletion results in a pro-inflammatory immune response at the feto-maternal interface. In addition to their function in suppressing pro-inflammatory responses in vitro, maternal CD71+ erythroid cells inhibit an aggressive allogeneic response directed against the fetus such as reduction in TNF-a production through arginase-2 activity and PD-1/PDL-1 interactions. Their depletion leads to the failure of gestation due to immunological rejection of the fetus. Similarly, fetal liver CD71+ erythroid cells exhibit immunosuppressive activity. Therefore, immunosuppression mediated by CD71+ erythroid cells on both sides (mother/fetus) is crucial for feto-maternal tolerance. Thus, our results reveal a previously unappreciated role for CD71+ erythroid cells in pregnancy and indicate that these cells mediate homeostatic immunosuppressive/immune-regulatory responses during pregnancy.

Erythroid suppressor cells promote feto-maternal tolerance through arginase-2 and PDL-1