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Biallelic mutations in IRF8 impair human NK cell maturation and function
Emily M. Mace, … , James R. Lupski, Jordan S. Orange
Emily M. Mace, … , James R. Lupski, Jordan S. Orange
Published November 28, 2016
Citation Information: J Clin Invest. 2017;127(1):306-320. https://doi.org/10.1172/JCI86276.
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Research Article Immunology Article has an altmetric score of 23

Biallelic mutations in IRF8 impair human NK cell maturation and function

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Abstract

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8–/–, but not Irf8+/–, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense.

Authors

Emily M. Mace, Venetia Bigley, Justin T. Gunesch, Ivan K. Chinn, Laura S. Angelo, Matthew A. Care, Sheetal Maisuria, Michael D. Keller, Sumihito Togi, Levi B. Watkin, David F. LaRosa, Shalini N. Jhangiani, Donna M. Muzny, Asbjørg Stray-Pedersen, Zeynep Coban Akdemir, Jansen B. Smith, Mayra Hernández-Sanabria, Duy T. Le, Graham D. Hogg, Tram N. Cao, Aharon G. Freud, Eva P. Szymanski, Sinisa Savic, Matthew Collin, Andrew J. Cant, Richard A. Gibbs, Steven M. Holland, Michael A. Caligiuri, Keiko Ozato, Silke Paust, Gina M. Doody, James R. Lupski, Jordan S. Orange

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Figure 3

Stable impairment in NK cell terminal differentiation in patients with biallelic IRF8 mutations.

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Stable impairment in NK cell terminal differentiation in patients with b...
NK cell phenotype was evaluated by multiparametric FACS phenotyping. (A) Representative FACS plot of healthy donor control (WT/WT) and our proband (A201V/P224L). Lymphocytes were gated on FSC/SSC. Data shown are representative of 6 independent repeats. (B) Stable NKD (left) and increased CD56bright population (right) in our proband shown over time (dashed line) with healthy donor shown as reference (solid line) at multiple dates from 2004 to 2015 (x axis). Single time point analysis of A201V/WT (unrelated, open diamond), A179V/WT (open triangle), an unrelated R83C/R291Q compound-heterozygous patient (solid inverted triangle), and a K108E/K108E patient (solid diamond) is also shown. (C) Percentage of CD56+CD3− NK cells within the lymphocyte gate is shown for 4 normal controls, our proband at 4 independent time points, 3 unrelated heterozygous IRF8 mutation patients, an unrelated compound-heterozygous patient, and a K108E/K108E patient. (D) Percentage of CD56bright NK cells within the NK cell compartment is shown for the cohort described in C. (E) FACS phenotyping of heterozygous, compound-heterozygous, and homozygous IRF8 patients. For intracellular staining, mononuclear cells were stimulated (S) with PMA and ionomycin in the presence of brefeldin A or incubated without stimulation (U) before fixation, permeabilization, and detection of intracellular effector molecules. (F) Expression of IFN-γ (after PMA/ionomycin stimulation) and perforin and CD16 in unstimulated NK cells from patients and healthy donors gated on CD56dim and CD56bright subsets. Shown is mean ± SD of 3 independent experiments for perforin and CD16 in healthy donor and A201V/P224L patient; a single experiment is shown for the K108E/K108E patient and IFN-γ detection from all subjects. *P < 0.05 by unpaired Student’s t test. (G) Cytokine secretion from healthy donor (HD) or A201V/P224L patient (Pt) detected by cytokine bead array from PBMCs stimulated for 4 hours by nonautologous EBV-transformed B cells in lytic cycle.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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