Helios enhances the preferential differentiation of human fetal CD4+ naïve T cells into regulatory T cells

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Science Immunology  22 Nov 2019:
Vol. 4, Issue 41, eaav5947
DOI: 10.1126/sciimmunol.aav5947

Helios lights the way to immunotolerance

Fetal naïve T cells are more apt than their adult counterparts to differentiate into regulatory T (Treg) cells after stimulation through the T cell receptor. Ng et al. investigated the origin of this bias using transcriptional and epigenetic profiling to compare fetal and adult naïve T cells with induced Treg cells. Expression of the Treg-associated transcription factor Helios by most fetal naïve T cells, but not adult naïve T cells, suggested that Helios might have a key role. CRISPR-Cas9–mediated deletion of Helios in fetal naïve T cells impaired their ability to differentiate into induced Treg cells in the absence of exogenous TGF-β. These findings lay the groundwork for development of new translational approaches to coax adult naïve T cells to differentiate into stable Treg cells.


T cell receptor (TCR) stimulation and cytokine cues drive the differentiation of CD4+ naïve T cells into effector T cell populations with distinct proinflammatory or regulatory functions. Unlike adult naïve T cells, human fetal naïve CD4+ T cells preferentially differentiate into FOXP3+ regulatory T (Treg) cells upon TCR activation independent of exogenous cytokine signaling. This cell-intrinsic predisposition for Treg 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 Treg cells that are inactive in adult naïve T cells and show that fetal-derived induced Treg (iTreg) cells retain this transcriptional program. We show that a subset of Treg-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 iTreg cells maintain Helios expression. CRISPR-Cas9 ablation of Helios in fetal naïve T cells impaired their differentiation into iTreg cells upon TCR stimulation, reduced expression of immunosuppressive genes in fetal iTreg cells such as IL10, and increased expression of proinflammatory genes including IFNG. Consequently, Helios knockout fetal iTreg 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 Treg function. The Treg-biased programs identified within fetal naïve T cells could potentially be used to engineer enhanced iTreg populations for adoptive cellular therapies.

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