Loss-of-function mutation in <em>IKZF2</em> leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells
Hetemäki, Iivo; Kaustio, Meri; Kinnunen, Matias; Heikkilä, Nelli; Keskitalo, Salla; Nowlan, Kirsten; Miettinen, Simo; Sarkkinen, Joona; Glumoff, Virpi; Andersson, Noora; Kettunen, Kaisa; Vanhanen, Reetta; Nurmi, Katariina; Eklund, Kari K.; Dunkel, Johannes; Mäyränpää, Mikko I.; Schlums, Heinrich; Arstila, T. Petteri; Kisand, Kai; Bryceson, Yenan T.; Peterson, Pärt; Otava, Ulla; Syrjänen, Jaana; Saarela, Janna; Varjosalo, Markku; Kekäläinen, Eliisa (2021-11-26)
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). https://doi.org/10.1126/sciimmunol.abe3454
© 2021 American Association for the Advancement of Science. The final authenticated version is available online at https://doi.org/10.1126/sciimmunol.abe3454.
https://rightsstatements.org/vocab/InC/1.0/
https://urn.fi/URN:NBN:fi-fe2022032825536
Tiivistelmä
Abstract
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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