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Aire-expressing cells defend the fetus: The normal maternal immune system adapts to pregnancy by learning to tolerate both allogeneic paternal and pregnancy-associated antigens expressed by the fetus and placenta. Gillis-Buck et al. investigated the contribution of cells expressing the autoimmune regulator (Aire) gene to maintaining fetal health using a mouse model in which Aire-expressing cells were deleted during early pregnancy. Ablation of Aire-expressing cells did not impair fetal implantation but resulted in intrauterine fetal growth restriction during both allogeneic and syngeneic pregnancies associated with increased activation of effector T cells. Selective deletion of extrathymic Aire-expressing cells (eTACs) while preserving Aire-expressing thymic epithelial cells revealed that eTACs are required for maintaining tolerance and fetal health. These findings demonstrate an unanticipated role for eTACs as guardians of fetal health during pregnancy. Healthy pregnancy requires tolerance to fetal alloantigens as well as syngeneic embryonic and placental antigens. Given the importance of the autoimmune regulator (Aire) gene in self-tolerance, we investigated the role of Aire-expressing cells in maternal-fetal tolerance. We report that maternal ablation of Aire-expressing (Aire+) cells during early mouse pregnancy caused intrauterine growth restriction (IUGR) in both allogeneic and syngeneic pregnancies. This phenotype is immune mediated, as IUGR was rescued in Rag1-deficient mice, and involved a memory response, demonstrated by recurrence of severe IUGR in second pregnancies. Single-cell RNA sequencing demonstrated that Aire+ cell depletion in pregnancy results in expansion of activated T cells, particularly T follicular helper cells. Unexpectedly, selective ablation of either Aire-expressing medullary thymic epithelial cells or extrathymic Aire-expressing cells (eTACs) mapped the IUGR phenotype exclusively to eTACs. Thus, we report a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis and demonstrate that eTACs protect the conceptus from immune-mediated IUGR. [ABSTRACT FROM AUTHOR]