Sunday, May 18, 2025
5/18/2025
Parity, paternity and pregnancy outcomes - Abstract. Prematurity remains the leading cause of infant mortality, responsible for well over 1 million deaths each year. Another 1.9 million babies are estimated to die in utero from stillbirth. We do not have effective cures because our understanding of how pregnancy works remains rudimentary. Important clues come from human epidemiological studies highlighting protective benefits of prior pregnancy against complications in future pregnancy, and the partner specificity of these effects. For example, the risk of preeclampsia is sharply reduced in women with prior healthy pregnancy, but rebounds with a change in paternity in subsequent pregnancy. Partner-specific resiliency against pregnancy complications is reproduced in mice using inbred strains expressing defined MHC haplotype or other model antigens for siring first and subsequent pregnancies. These parallels establish our scientific premise that investigating how fetal-expressed antigens are recognized and remembered by mothers will efficiently unveil essential new knowledge on how pregnancy works, and urgently needed strategies for improving pregnancy outcomes. Pregnancy in humans and mice each stimulate expansion of immune suppressive maternal CD4 T cells that express the FOXP3 transcriptional regulator, called regulatory T cells (Tregs). Tracking maternal CD4 cells using antigen-specific tools show selective Treg expansion among cells with fetal-specificity. In turn, resiliency against pregnancy complications is associated with postpartum persistence fetal-specific “memory” Tregs, establishing an instructive framework for investigating how mothers immunologically remember their children. Our recent studies tracking maternal CD4 cells using FOXP3 lineage fate tracking reporter mice further show a large proportion (40-70%) of fetal-specific Tregs loose FOXP3 expression after parturition. These FOXP3-negative “exTregs” are essential for enhanced resiliency against complications in future pregnancy, because their depletion overrides the protective benefits of adoptively transferred postpartum donor splenocytes. At the same time, these findings also highlight exciting new gaps in knowledge regarding the interplay between FOXP3 expression plasticity, fetal tolerance and pregnancy outcomes. These knowledge gaps, directly aligned with the goals of RFA-AI-23-027, Immune mechanisms at the maternal-fetal interface, will be addressed through the following specific aims designed to further investigate our overall hypothesis that mothers remember not only through fetal-specific FOXP3+ Treg memory, but also via exTregs with distinct phenotypic and functional features: Establish the suppressive molecules utilized by exTregs and FOXP3+ Tregs for enhanced resiliency against pregnancy complications (Aim 1), Investigate maternal CD4 cell differentiation after fractured fetal tolerance induced pregnancy complications (Aim 2), and Determine whether pregnancy primed exTregs are committed for FOXP3 re- expression or liable to proinflammatory differentiation with fetal antigen re-stimulation in the physiologically relevant non-tolerogenic context of solid organ transplantation (Aim 3).
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