A disrupted FOXP3 transcriptional signature underpins regulatory T cells insufficiency in early pregnancy failure
Regulatory T (Treg) cell defects are implicated in disorders of embryo implantation and placental development, but the origins of Treg cell dysfunction are unknown. Here, we comprehensively analyzed the phenotypes and transcriptional profile of peripheral blood Treg cells in individuals with early pregnancy failure (EPF). Compared to fertile subjects, EPF subjects had 32% fewer total Treg cells and 54% fewer CD45RA+CCR7+ naïve Treg cells amongst CD4+ T cells, accompanied by lower Treg:Th1 and Treg:Th17 ratios. An altered phenotype with reduced transcription factor FOXP3 and suppressive marker CTLA4 was also evident. RNAseq demonstrated an aberrant gene expression profile, with upregulation of pro-inflammatory genes including CSF2, IL4, IL17A, IL21, and IFNG, in EPF Treg cells. In silico analysis revealed 25% of the Treg cell dysregulated genes are targets of FOXP3 control. We conclude that Treg cell defects in EPF can arise due to loss of lineage fidelity associated with impaired FOXP3 regulation. Overall design: Transcriptional profiling of peripheral blood Treg cells in individuals with early pregnancy failure (EPF) compared to fertile subjects.