Reproductive immunology

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Permissive Epigenetic Marks at Regulatory T Cell Signature Genes in Fetal Naïve CD4+ T Cells Prime their Differentiation into Regulatory T Cells

Friday, June 16
5:00 PM - 5:15 PM

The developing human fetal immune system achieves immune tolerance through active generation of a prevalent population of CD25+FoxP3+ regulatory T (Treg) cells present in secondary lymphoid organs. Crucially, fetal CD4+ naïve T cells preferentially differentiate into Treg cells upon T cell receptor (TCR) stimulation ex vivo. In addition to the expression of the lineage-determining factor FOXP3, commitment to the Treg cell fate is preceded by the acquisition of permissive epigenetic modification at Treg cell-specific super-enhancers (Treg-SE) associated with the transcriptional control of Treg signature genes. Through ATACseq (Assay for Transposase-Accessible Chromatin Sequencing) and H3K27ac ChIPseq (Chromatin Immunoprecipitation Sequencing), we show that fetal naïve CD4+ T cells share large regions of chromatin accessibility with adult Treg cells that are absent in adult naïve CD4+ T cells. A significant proportion of these regions maps within Treg-SE and are associated with Treg signature genes such as IKZF2 (Helios). We show that Helios is highly expressed in fetal and not in adult naïve CD4+ T cells. Cas9-mediated Helios knockdown in fetal naïve CD4+ T cells results in the reduced induction of CD25+FOXP3+ Treg cells, indicating a potent contribution of Helios expression in enhancing fetal Treg cell differentiation. The establishment of permissive epigenetic marks at Treg-SE within fetal naïve T cells might thus underlie the predisposition for fetal Treg cell differentiation. Further work in this project will correlate these permissive chromatin regions with active gene transcription through RNA sequencing, and validate their key role in driving fetal Treg cell differentiation.

Melissa Ng

Ph.D. Candidate
University of California, San Francisco

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Trevor Burt

Assistant Professor
University of California, San Francisco

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Permissive Epigenetic Marks at Regulatory T Cell Signature Genes in Fetal Naïve CD4+ T Cells Prime their Differentiation into Regulatory T Cells



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