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

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+ 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239865 | GEO | 2024/01/28

REPOSITORIES: GEO

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Loss of Foxp3-driven epigenetic modification leads to regulatory T cell insufficiency

Project description:Regulatory T cells (Tregs) are responsible for limiting autoimmunity and chronic inflammation. Foxp3 is a transcription factor that acts as a master regulator of Treg development and function. A serendipitous observation led to the realization that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg development and in vitro function is not significantly altered in Foxp3gfp NOD and C57BL/6 mice, Treg fitness function in inflammatory environments is perturbed and TGF?-induced Treg development reduced. Foxp3gfpis unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which leads to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this leads to an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg insufficiency that causes autoimmunity in prone environments. 16 samples overall split between 2 genotypes (wild type and Foxp3 knock in) and two cell types (Tregs and Tconv)

2012-12-07 | E-GEOD-35164 | biostudies-arrayexpress

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2012-12-07 | GSE35164 | GEO

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2017-02-15 | PXD001906 | Pride

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