A HEXIM1-AIRE transcriptional counter-balance in trophoblasts regulates maternal-fetal mucosal immunity in pregnancy (MUC7P.755)

Abstract Trophoblasts are gatekeepers at maternal-fetal mucosal interface, but trophoblast-derived molecules that initiate and maintain maternal-fetal mucosal immunity are not fully understood. We found that HEXIM1, an inhibitor of P-TEFb essential for eukaryotic RNA Pol II-mediated transcription, is highly expressed in human villous and extravillous trophoblasts. Hexim1-/- mouse placentas exhibit abnormal placental immunity characterized by increased maternal leukocyte and T cell infiltration, a paucity of spiral arteries and reduced placental size. HEXIM1 interacts in trophoblasts with AIRE, a protein critical for central and peripheral immune tolerance, via 7SK snRNA. Such interaction is further dependent on the nuclear localization domains of HEXIM1 and AIRE. Extravillous trophoblasts in human preterm labor with placental inflammation have reduced HEXIM1 and increased AIRE expression. Silencing HEXIM1 in trophoblasts led to increased Treg induction by trophoblasts. Our findings identify trophoblasts as a new type of extrathymic AIRE-expressing immunoregulatory cell, reveal a novel function of epithelial cells in mucosal immune regulation via AIRE-mediated Treg induction, suggest HEXIM1 and AIRE establish a transcriptional counterbalance in trophoblasts to maintain maternal-fetal mucosal immunity in pregnancy by regulating P-TEFb and Pol II, and promote a better understanding of how certain pathogens, such as HIV-1, perturb mucosal homeostasis after hijacking the HEXIM1 machinery.