High-dimensional multiomics reveals perturbations to IL-6/IL-6R axis and RUNX3 in CD4 + T cells during third trimester pregnancy

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ABSTRACT Objectives CD4 + T cells play key roles in regulating immune responses during pregnancy, therefore we aimed to understand the CD4 + T cell surface proteome and transcriptome during pregnancy. Methods CD4 + T cells were analysed in blood and decidua from term-pregnancies (>37 weeks), and non-pregnant blood. >350 surface proteins were screened via flow cytometry, and transcriptomes were analysed using single-cell RNA sequencing with >130 CITE-seq barcoded antibodies. Results Surface protein screening identified changes to ILT4/CD85d, CD9, IFN-γ receptor β-chain, CX3CR1 and CCR5 in the pregnant blood and decidual CD4 + T cells. CX3CR1 and CCR5 had the highest expression on the effector-memory T cell (T EM ) subset in the blood, with expression consistent across subsets in decidua. CD126/IL-6R was lower in pregnant blood and decidual CD4 + T cells, while scRNAseq identified enrichment in the IL-6R signalling pathway in naive CD4 + T cells in pregnant blood. Both sIL-6R and IL-6 concentrations were increased in plasma during pregnancy, suggesting perturbations to the IL-6/IL-6R signalling axis. Meanwhile, decidual CD4 + T cells had increased expression of transcription factor RUNX3 in the CD69 + tissue-resident-like subset. Conclusions Our findings demonstrate altered molecular expression in CD4 + T cells during pregnancy. This provides important mechanistic insight of their adaptation and regulation during placental development, which may drive placental dysfunction or pregnancy complications including preeclampsia, fetal growth restriction and stillbirth. These new data may inform future studies that focus on determining the significance of differentially- expressed immune features in pregnancy to identify potential targets for immune modulation to treat pregnancy complications and infections.