Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity.

Helios, a member of the Ikaros family of transcription factors, is predominantly expressed in developing thymocytes, activated T cells, and regulatory T cells (T). Studies in mice have emphasized its role in maintenance of T immunosuppressive functions by stabilizing Foxp3 expression and silencing the locus. However, its contribution to human immune homeostasis and the precise mechanisms by which Helios regulates other T cell subsets remain unresolved. Here, we investigated a patient with recurrent respiratory infections and hypogammaglobulinemia and identified a germline homozygous missense mutation in encoding Helios (p.Ile325Val). We found that Helios retains DNA binding and dimerization properties but loses interaction with several partners, including epigenetic remodelers. Whereas patient T showed increased IL-2 production, patient conventional T cells had decreased accessibility of the locus and consequently reduced IL-2 production. Reduced chromatin accessibility was not exclusive to the locus but involved a variety of genes associated with T cell activation. Single-cell RNA sequencing of peripheral blood mononuclear cells revealed gene expression signatures indicative of a shift toward a proinflammatory, effector-like status in patient CD8 T cells. Moreover, patient CD4 T cells exhibited a pronounced defect in proliferation with delayed expression of surface checkpoint inhibitors, suggesting an impaired onset of the T cell activation program. Collectively, we identified a previously uncharacterized, germline-encoded inborn error of immunity and uncovered a cell-specific defect in Helios-dependent epigenetic regulation. Binding of Helios with specific partners mediates this regulation, which is ultimately necessary for the transcriptional programs that enable T cell homeostasis in health and disease.