Back to Search
Start Over
Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells.
- Source :
- Science Immunology; 2019, Vol. 4 Issue 41, p1-19, 19p, 8 Graphs
- Publication Year :
- 2019
-
Abstract
- T cell receptor (TCR) stimulation and cytokine cues drive the differentiation of CD4<superscript>+</superscript> naïve T cells into effector T cell populations with distinct proinflammatory or regulatory functions. Unlike adult naïve T cells, human fetal naïve CD4<superscript>+</superscript> T cells preferentially differentiate into FOXP3<superscript>+</superscript> regulatory T (T<subscript>reg</subscript>) cells upon TCR activation independent of exogenous cytokine signaling. This cell-intrinsic predisposition for T<subscript>reg</subscript> differentiation is implicated in the generation of tolerance in utero; however, the underlying mechanisms remain largely unknown. Here, we identify epigenetic and transcriptional programs shared between fetal naïve T and committed T<subscript>reg</subscript> cells that are inactive in adult naïve T cells and show that fetal-derived induced T<subscript>reg</subscript> (iT<subscript>reg</subscript>) cells retain this transcriptional program. We show that a subset of T<subscript>reg</subscript>-specific enhancers is accessible in fetal naïve T cells, including two active superenhancers at Helios. Helios is expressed in fetal naïve T cells but not in adult naïve T cells, and fetal iT<subscript>reg</subscript> cells maintain Helios expression. CRISPR-Cas9 ablation of Helios in fetal naïve T cells impaired their differentiation into iT<subscript>reg</subscript> cells upon TCR stimulation, reduced expression of immunosuppressive genes in fetal iT<subscript>reg</subscript> cells such as IL10, and increased expression of proinflammatory genes including IFNG. Consequently, Helios knockout fetal iT<subscript>reg</subscript> cells had reduced IL-10 and increased IFN-γ cytokine production. Together, our results reveal important roles for Helios in enhancing preferential fetal Treg differentiation and fine-tuning eventual T<subscript>reg</subscript> function. The T<subscript>reg</subscript>-biased programs identified within fetal naïve T cells could potentially be used to engineer enhanced iT<subscript>reg</subscript> populations for adoptive cellular therapies. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 24709468
- Volume :
- 4
- Issue :
- 41
- Database :
- Complementary Index
- Journal :
- Science Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 164981970
- Full Text :
- https://doi.org/10.1126/sciimmunol.aav5947