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.

健康怀孕需要对胎儿同种异体抗原以及同基因胚胎和胎盘抗原的耐受性。鉴于自身免疫调节因子 ( Aire ) 基因在自身耐受中的重要性，我们研究了表达Aire的细胞在母胎耐受中的作用。我们报告说，小鼠早期妊娠期间对表达Aire ( Aire ⁺ ) 细胞的母体消融导致同种异体和同基因妊娠的宫内生长受限 (IUGR)。这种表型是免疫介导的，因为 IUGR 在 Rag1 缺陷小鼠中获救，并涉及记忆反应，这在第二次怀孕时严重 IUGR 的复发证明了这一点。单细胞 RNA 测序表明Aire ⁺妊娠期细胞耗竭导致活化 T 细胞扩增，尤其是 T 滤泡辅助细胞。出乎意料的是，表达 Aire 的髓质胸腺上皮细胞或表达胸腺外 Aire 的细胞 (eTAC) 的选择性消融将IUGR表型仅映射到 eTAC。因此，我们报告了一种先前未描述的维持母胎免疫稳态的机制，并证明 eTACs 可以保护胎体免受免疫介导的 IUGR 的影响。