University of Oulu

Tala Shahin, Hye Sun Kuehn, Mohamed R. Shoeb, Lisa Gawriyski, Sarah Giuliani, Peter Repiscak, Birgit Hoeger, Özlem Yüce Petronczki, Sevgi Köstel Bal, Samaneh Zoghi, Jasmin Dmytrus, Davide Seruggia, Irinka Castanon, Nima Rezaei, Markku Varjosalo, Florian Halbritter, Sergio D. Rosenzweig, Kaan Boztug, Germline biallelic mutation affecting the transcription factor Helios causes pleiotropic defects of immunity, Science Immunology, 6, 65, (2021).

Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells

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Author: Hetemäki, Iivo1; Kaustio, Meri2; Kinnunen, Matias3;
Organizations: 1Translational Immunology Research Program, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
2Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
3Institute of Biotechnology, HiLIFE Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
4Research Unit of Biomedicine, University of Oulu, Oulu, Finland
5Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
6Department of Clinical Genetics and HUSLAB Laboratory of Genetics, Helsinki University Hospital, Helsinki, Finland
7Department of Rheumatology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
8Orton Orthopaedic Hospital of the Orton Foundation, Helsinki, Finland
9Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
10Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
11Broegelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway
12Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estoni
13Infectious Disease Unit, Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
14Centre for Molecular Medicine Norway (NCMM), University of Oslo, Oslo, Norway
15Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
Format: article
Version: accepted version
Access: open
Online Access: PDF Full Text (PDF, 12.6 MB)
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Language: English
Published: American Association for the Advancement of Science, 2021
Publish Date: 2022-03-28


The Ikaros family transcription factors regulate lymphocyte development. Loss-of-function variants in IKZF1 cause primary immunodeficiency, but Ikaros family members IKZF2 and IKZF3 have not yet been associated with immunodeficiency. Here, we describe a pedigree with a heterozygous truncating variant in IKZF2, encoding the transcriptional activator and repressor Helios, which is highly expressed in regulatory T cells and effector T cells, particularly of the CD8⁺ T cell lineage. Protein-protein interaction analysis revealed that the variant abolished heterodimerization of Helios with Ikaros and Aiolos and also prevented Helios binding to members of the Mi-2/NuRD chromatin remodeling complex. Patients carrying the IKZF2 variant presented with a combined immunodeficiency phenotype characterized by recurrent upper respiratory infections, thrush and mucosal ulcers, and chronic lymphadenopathy. With extensive immunophenotyping, functional assays, and transcriptional analysis, we show that reduced Helios expression was associated with chronic T cell activation and increased production of proinflammatory cytokines both in effector and regulatory T cells. Lymph node histology from patients indicated dysregulated germinal center reactions. Moreover, affected individuals displayed a profound reduction in circulating MAIT cell numbers. In summary, we show that this previously undescribed loss-of-function variant in Helios leads to an immunodeficiency with signs of immune overactivation.

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Series: Science immunology
ISSN: 2470-9468
ISSN-E: 2470-9468
ISSN-L: 2470-9468
Volume: 6
Issue: 65
Article number: e3454
DOI: 10.1126/sciimmunol.abe3454
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
Copyright information: © 2021 American Association for the Advancement of Science. The final authenticated version is available online at