Helios enhances the preferential differentiation of human fetal CD4⁺ naïve T cells into regulatory T 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 (T_reg) cells upon TCR activation independent of exogenous cytokine signaling. This cell-intrinsic predisposition for T_reg 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_reg cells that are inactive in adult naïve T cells and show that fetal-derived induced T_reg (iT_reg) cells retain this transcriptional program. We show that a subset of T_reg-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_reg cells maintain Helios expression. CRISPR-Cas9 ablation of Helios in fetal naïve T cells impaired their differentiation into iT_reg cells upon TCR stimulation, reduced expression of immunosuppressive genes in fetal iT_reg cells such as IL10, and increased expression of proinflammatory genes including IFNG Consequently, Helios knockout fetal iT_reg cells had reduced IL-10 and increased IFN-γ cytokine production. Together, our results reveal important roles for Helios in enhancing preferential fetal T_reg differentiation and fine-tuning eventual T_reg function. The T_reg-biased programs identified within fetal naïve T cells could potentially be used to engineer enhanced iT_reg populations for adoptive cellular therapies.

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