期刊
SCIENCE IMMUNOLOGY
卷 6, 期 61, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abf1968
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类别
资金
- NIH [R01 A125452, R01 AI145858]
- Howard Hughes Medical Research Fellows Program
- UCSF Sandler PSSP and ASTS Fellowship
Research showed that depletion of Aire(+) cells during pregnancy leads to an expansion of activated T cells, particularly T follicular helper cells. The elimination of Aire-expressing cells results in immune-mediated intrauterine growth restriction (IUGR), indicating a previously undescribed mechanism for the maintenance of maternal-fetal immune homeostasis.
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.
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