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

We studied a patient with recurrent respiratory infections and hypogammaglobulinemia and identified a germline homozygous missense mutation in IKZF2 encoding Helios (p.Ile325Val). We show that HeliosI325V retains DNA-binding and dimerization properties, but loses interaction with several partners, including epigenetic remodelers HDAC1, HDAC3 and the ATAC complex. Single-cell RNA-sequencing of peripheral blood mononuclear cells revealed gene expression signatures indicative of a shift towards pro-inflammatory, effector-like status in the patient’s T cells. We observed an upregulation of the anti-inflammatory gene, TSC22D3, encoding the glucocorticoid-induced leucine zipper (GILZ), whose expression was reported to increase upon IL-2 deprivation. We validated this finding in primary T cells, where we observed a pronounced reduction in IL-2 production upon their stimulation, together with a defect in their ability to proliferate, rendering them more anergic. Collectively, we identify a novel germline-encoded inborn error of immunity and define a role for Helios in conventional T cells, whereby interactions with specific binding partners is necessary to mediate the transcriptional programs that enable T-cell homeostasis in health and disease.

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Dataset ID Description Technology Samples
EGAD00001008370 Illumina HiSeq 4000 3
EGAD00001008371 Illumina HiSeq 4000 24
EGAD00001008372 Illumina HiSeq 4000 5
Publications Citations
Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity.
Sci Immunol 6: 2021 eabe3981
7
Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation.
Blood Adv 6: 2022 2444-2451
11