Defective induction of regulatory B cells by decidua stromal cells underlies the pathogenesis of preterm birth (P3213)

Abstract Preterm birth is the leading cause of mortality and morbidity of newborns. Many maternal autoimmune conditions that predispose to preterm birth involve the dysregulation of autoreactive B cells that contribute to disease pathogenesis. Despite the fundamental roles of B cells as effectors and regulators of immunity, their functions in pregnancy are poorly understood. We found that human B cells undergo activation, class switching, memory and plasmacytoid differentiation in the decidua in situ. Preterm decidua harbors increased numbers of total B cells and B-1 cells but diminished numbers of IL-10-producing regulatory B cells in vivo. Furthermore, stromal cells in preterm decidua, as compared to those in term decidua, stimulate increased B cell activation and the differentiation of potentially autoreactive B cells, but are defective in inducing IL-10 expression by B cells. These results demonstrate that preterm birth involves abnormal B cell functions at the maternal-fetal interface, whereby decidua stromal dysfunction engenders unique populations of B cells with increased autoreactivity but diminished regulatory functions, and suggest that regulatory B cells are important for the maintenance of normal pregnancy. These studies provide insights into the functions of B cells at the maternal-fetal interface during pregnancy and inform the design of B cell-targeted therapies to treat preterm birth and other pregnancy complications involving B cell dysfunction.</jats:p

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.</jats:p