[F31] Defining the role of RORγt-lineage antigen-presenting cells in maternal-fetal tolerance

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PROJECT SUMMARY/ABSTRACT Successful pregnancy requires the maternal immune system to tolerate paternal alloantigens expressed by the fetus and placenta while maintaining protective immunity against pathogens. Pregnancy complications associated with maternal immune dysregulation, including preeclampsia, recurrent pregnancy loss, preterm birth, and intrauterine growth restriction (IUGR), remain major causes of maternal and neonatal morbidity. RORγt-lineage antigen-presenting cells (R-APCs) are a specialized tolerogenic population that promote peripheral induction of antigen-specific regulatory T cells (Tregs) to commensal and dietary antigens in gut-draining lymph nodes, suggesting that analogous mechanisms may support tolerance to the semi-allogeneic fetus. Previous work has shown that extrathymic Aire-expressing cells, a rare subset of R-APCs, are required for healthy pregnancy and maternal immune homeostasis. Preliminary data now demonstrate that selective disruption of antigen presentation (MHCII), TGFβ activation (Itgb8), or Aire expression within maternal R-APCs results in embryo growth restriction during allogeneic, but not syngeneic, pregnancies, indicating a critical and context-dependent role for R-APCs in maternal-fetal tolerance. This project tests the hypothesis that maternal R-APCs are necessary to maintain immune homeostasis in uterine-draining lymph nodes and to induce alloantigen-specific Tregs that restrain pathogenic effector T cell responses to fetal-derived paternal antigens. Aim 1 will determine the necessity of maternal R-APCs for healthy pregnancy by comparing pregnancy outcomes and maternal T cell phenotypes in uterine-draining lymph nodes of RORγt-lineage conditional knockout dams (MHCII, Itgb8, and Prdm16) and wild-type littermates after allogeneic versus syngeneic mating, including assessment of fetal and postnatal growth. Aim 2 will define the mechanisms by which maternal R-APCs mediate tolerance by using a tractable neoantigen model (Act-mOVA-2W1S sires, OT-I/OT-II adoptive transfer, and 2W1S tetramers) to quantify alloantigen-specific maternal Treg and effector responses in vivo and in vitro. Dams will be treated with antibiotics to distinguish direct defects in tolerance to paternal alloantigen from secondary effects of dysbiosis. Aim 3 will define the role of Aire in maternal R-APCs during pregnancy by testing whether Aire gene expression is required for alloantigen-specific Treg induction and healthy pregnancy outcomes. Single-cell RNA-seq and ATAC-seq on sorted R-APCs from conditional Aire knockout dams and WT littermates will define Aire-dependent transcriptional and epigenetic programs in maternal R-APCs. Together, these studies will elucidate how R-APC dysfunction leads to IUGR and aberrant maternal T cell responses and will identify molecular pathways of antigen-specific tolerance in pregnancy with broad implications for immune-mediated infertility, IUGR, transplantation, autoimmunity, and allergy. Istituzione: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO PI: Eva Mae Gillis-Buck Progetto: 1F31AI202777-01

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Source: reporter.nih.gov