A disrupted FOXP3 transcriptional signature underpins systemic regulatory T cell insufficiency in early pregnancy failure

Lachlan M Moldenhauer; Kerrie L Foyle; Jasmine J Wilson; Ying Y Wong; David J Sharkey; Ella S Green; Simon C Barry; M Louise Hull; Sarah A Robertson

doi:10.1016/j.isci.2024.108994

A disrupted FOXP3 transcriptional signature underpins systemic regulatory T cell insufficiency in early pregnancy failure

iScience. 2024 Jan 23;27(2):108994. doi: 10.1016/j.isci.2024.108994. eCollection 2024 Feb 16.

Authors

Lachlan M Moldenhauer¹, Kerrie L Foyle¹, Jasmine J Wilson¹, Ying Y Wong¹, David J Sharkey¹, Ella S Green¹, Simon C Barry¹, M Louise Hull², Sarah A Robertson¹

Affiliations

¹ Robinson Research Institute and School of Biomedicine, The University of Adelaide, Adelaide, SA, Australia.
² Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.

Abstract

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⁺ naive Treg cells among CD4⁺ T cells, an altered Treg cell phenotype with reduced transcription factor FOXP3 and suppressive marker CTLA4 expression, and lower Treg:Th1 and Treg:Th17 ratios. RNA sequencing 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. We conclude that EPF is associated with systemic Treg cell defects arising due to disrupted FOXP3 transcriptional control and loss of lineage fidelity.

Keywords: Health sciences; Immunology; Pregnancy.