Innate Allorecognition at the Maternal-Fetal Interface

Pregnancy is a maternal balancing act. To guarantee optimal lifetime reproductive success, the mother must partition her resources between current and future pregnancies. Too little investment in the current pregnancy compromises fetal survival, while too much investment lowers lifetime reproductive success by compromising future pregnancies. We hypothesize here that immune system genes that encode activating and inhibitory allorecognition receptors on myeloid cells set the optimum by balancing the maternal alloimmune response at the maternal-fetal interface. Activating receptors limit trophoblast invasion and reduce maternal cost while inhibitory receptors exert an opposite effect, resulting in an optimal balance. We also hypothesize that disrupting the balance in either direction (in favor of the mother or in favor of the fetus) increases the risk of gestational disorders such as preeclampsia. We will focus on allorecognition receptors expressed on monocytes and macrophages that regulate the alloimmune response to transplanted organs but have not been previously studied in gestation. In Aim 1, we will test the hypotheses in mice by investigating the effect of deleting these receptors on the decidual immune landscape, trophoblast invasion, placental function, and reproductive success, and assess if this results in preeclampsia-like features. In Aim 2, we will test the hypotheses in humans by investigating the association between preeclampsia and a maternal-fetal mismatch in the polymorphic gene encoding one of these receptors that favors maternal myeloid cell activation. Particular attention will be paid to the likely divergence of the immunopathogenesis of early and late preeclampsia, which differ dramatically in placental pathology and effects on fetal growth. This grant proposal brings together transplant immunologists, reproductive biologists, and preeclampsia experts to execute the proposed aims.