Transplacental Innate Immune Training via Maternal Microbial Exposure: Role of XBP1-ERN1 Axis in Dendritic Cell Precursor Programming

Background: Maternal enviromnetal exposures during pregnancy can transplacentally train the developing fetal immune system. We have proviously shown that treatment of pregnant mice with the microbial-derived OM-85 can protect their offspring against allergic airways disease. Purpose: To characterise the cellular/molecular mechanisms underpinning this protection, focusing on the fetal bone marrow as a potential mechanistic target. Methods: Pregnant mice were orally treated with OM-85 from gestation day (GD) 9.5-17.5. Fetal bone marrow and thymus was collected from OM-85 treated and non-treated mothers at GD18.5. Cellular and molecular profiles were characterised by multi-colour flow cytometry and transcriptomics (RNA-Seq) respectively.. Molecular profiling utilised upstream regulator analysis .Protein-level validation of upstream regulator analysis results was performed by multi-colour flow cytometry. Results: Maternal OM-85 treatment induces transplacental signals that manifest in fetal bone marrow as an enriched population of conventional dendric cells (cDC) displaying enhanced functional maturation. Moreover, the myeloid progenitor populations directly upstream of this cDC pool were significantly boosted in response to maternal treatment. Transcriptomic analysis of fetal bone marrow identified maternal OM-85-induced activation of X-box binding protein 1 (XBP1), with upregulation of active XBP1 localised to cDC precursors. Conclusions: Maternal OM-85 treatment during pregnancy transplacentally accelerates functional immunocompetence of fetal bone marrow cDCs and for the first time we identify the transcription factor XBP1 as a putative driver of this immune training mechanism. This study consisted of paired bone marrow (n=32) and thymus (n=32) samples from gestation day 18.5 fetuses from OM-85 treated or non-treated mothers. RNA-Seq profiles were generated by sequencing Illumina HiSeq2500, 50bp single-end reads, v4 chemistry.