Germline Biallelic Mutation Affecting the Transcription Factor Helios Causes Pleiotropic Defects of Immunity Publisher Pubmed



Shahin T^{1, 2, 3, 4} ; Kuehn HS⁵ ; Shoeb MR¹ ; Gawriyski L⁶ ; Giuliani S^{1, 2} ; Repiscak P¹ ; Hoeger B^{1, 2} ; Petronczki OY^{1, 2} ; Bal SK^{1, 2} ; Zoghi S^{1, 2} ; Dmytrus J^{1, 2} ; Seruggia D¹ ; Castanon I¹ ; Rezaei N^{7, 8, 9} Show All Authors Show Affiliations
Source: Science Immunology Published:2021

Abstract

Helios, a member of the Ikaros family of transcription factors, is predominantly expressed in developing thymocytes, activated T cells, and regulatory T cells (Tregs). Studies in mice have emphasized its role in maintenance of Treg immunosuppressive functions by stabilizing Foxp3 expression and silencing the Il2 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 IKZF2 encoding Helios (p.Ile325Val). We found that HeliosI325V retains DNA binding and dimerization properties but loses interaction with several partners, including epigenetic remodelers. Whereas patient Tregs showed increased IL-2 production, patient conventional T cells had decreased accessibility of the IL2 locus and consequently reduced IL-2 production. Reduced chromatin accessibility was not exclusive to the IL2 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. Copyright © 2021 The Authors, some rights reserved.