Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency
David Boutboul, … , Sylvain Latour, Sergio D. Rosenzweig
David Boutboul, … , Sylvain Latour, Sergio D. Rosenzweig
Published June 11, 2018
Citation Information: J Clin Invest. 2018;128(7):3071-3087. https://doi.org/10.1172/JCI98164.
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Research Article Genetics Immunology

Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency

Abstract

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

Authors

David Boutboul, Hye Sun Kuehn, Zoé Van de Wyngaert, Julie E. Niemela, Isabelle Callebaut, Jennifer Stoddard, Christelle Lenoir, Vincent Barlogis, Catherine Farnarier, Frédéric Vely, Nao Yoshida, Seiji Kojima, Hirokazu Kanegane, Akihiro Hoshino, Fabian Hauck, Ludovic Lhermitte, Vahid Asnafi, Philip Roehrs, Shaoying Chen, James W. Verbsky, Katherine R. Calvo, Ammar Husami, Kejian Zhang, Joseph Roberts, David Amrol, John Sleaseman, Amy P. Hsu, Steven M. Holland, Rebecca Marsh, Alain Fischer, Thomas A. Fleisher, Capucine Picard, Sylvain Latour, Sergio D. Rosenzweig

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Figure 3

Functional T cell defects associated with heterozygous IKZF1N159S/T mutations.

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Functional T cell defects associated with heterozygous IKZF1N159S/T muta...
(A–C) PBMCs from patients A1, C1, and G1 and healthy donor controls (Ctrl) were stimulated with indicated agonists for 6–7 days. (A) Cells stimulated (stim.) with plate-coated anti-CD3 at the indicated concentrations or with anti-CD3/CD28–coated beads. (B) Cells stimulated with plate-coated anti-CD3 at 0.05 μg/ml with or without IL-2. unstim., unstimulated. (C) Cells stimulated with plate-coated anti-CD3 at the indicated concentrations with or without IL-2. Proliferation was determined by dilution of CellTrace Violet dye analyzed by flow cytometry. Histograms showing cell divisions by dilution of the CellTrace Violet dye (A and B) and CD25 expression (C). Data are representative of 3 experiments. (D) Histograms from PHA-derived T cell blasts from patients A1, G1, and a healthy donor control (Ctrl) stimulated with (blue) or without (red) anti-CD3/CD28–coated beads (upper panels) or with PMA/ionomycin (iono; lower panels) for 24 hours. IL-2 (lower panels) and IFN-γ (upper panels) were measured with intracellular flow cytometry assays. Black dashed line indicates isotype control. Data are representative of 2 experiments. (E) PBMCs from patients C1, D1, and G1 and healthy donor controls (Ctrls) were stimulated with anti-CD3/CD28–coated beads for 24 hours. Cell-free supernatants were harvested, and cytokines (IL-2, TNF-α, IL-6, and IFN-γ) were measured with the Luminex 200 System. Data indicate the mean of replicate sample for C1 (n = 2), D1 (n = 1), and G1 (n = 1) compared with 6–9 different healthy donor controls (mean ± SD). The n values represent the number of replicates. (F) PBMCs from patients C1, D1, G1, and 2 paired healthy donor controls (Ctrls) were stimulated with PMA/ionomycin for 6 hours. IL-2, IFN-γ, and IL-4 (for Th1/2 evaluation) and IL-17A (for Th17 evaluation) were measured with intracellular flow cytometry assays. Data represent the percentage of the cells positive for the indicated cytokine among CD4+ T cells. Data are issued from 2 experiments performed in patient C1 and 1 experiment from D1 and G1.