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Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

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Hoshino, Akihiro | Boutboul, David | Zhang, Yuan | Kuehn, Hye Sun | Hadjadj, Jerôme | Özdemir, Nihal | Celkan, Tiraje | Walz, Christoph | Picard, Capucine | Lenoir, Christelle | Mahlaoui, Nizar | Klein, Christoph | Peng, Xiao | Azar, Antoine | Reigh, Erin | Cheminant, Morgane | Fischer, Alain | Rieux-Laucat, Frédéric | Callebaut, Isabelle | Hauck, Fabian | Milner, Joshua | Rosenzweig, Sergio | Latour, Sylvain

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline IKZF1 haploinsufficient ( IKZF1 HI ) and dominant-negative ( IKZF1 DN ) variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous IKZF1 variants (R183C/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (T H ) skewing toward T H 2, low numbers of regulatory T cells (T reg ), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1 HI and IKZF1 DN , IKZF1 R183H/C proteins showed increased DNA binding associated with increased gene expression of T H 2 and PC differentiation, thus demonstrating that IKZF1 R183H/C behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T H 2 and PC abnormalities caused by IKZF1 R183H/C . These data extend the spectrum of pathological mechanisms associated with IKZF1 deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.

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