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Biallelic mutations in IRF8 impair human NK cell maturation and function

Lookup NU author(s): Dr Venetia BigleyORCiD, Professor Matthew CollinORCiD, Professor Andrew Cant



This is the final published version of an article that has been published in its final definitive form by American Society for Clinical Investigation, 2017.

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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 CD56(dim) NK cells and an increase in the frequency of the immature CD56(bright) 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.

Publication metadata

Author(s): Mace EM, Bigley V, Gunesch JT, Chinn IK, Angelo LS, Care MA, Maisuria S, Keller MD, Togi S, Watkin LB, LaRosa DF, Jhangiani SN, Muzny DM, Stray-Pedersen A, Akdemir ZC, Smith JB, Hernandez-Sanabria M, Le DT, Hogg GD, Cao TN, Freud AG, Szymanski EP, Savic S, Collin M, Cant AJ, Gibbs RA, Holland SM, Caligiuri MA, Ozato K, Paust S, Doody GM, Lupski JR, Orange JS

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Investigation

Year: 2017

Volume: 127

Issue: 1

Pages: 306-320

Print publication date: 03/01/2017

Online publication date: 28/11/2016

Acceptance date: 18/10/2016

Date deposited: 20/06/2017

ISSN (print): 0021-9738

ISSN (electronic): 1558-8238

Publisher: American Society for Clinical Investigation


DOI: 10.1172/JCI86276


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Funder referenceFunder name
Jeffrey Modell Foundation
Genomic and RNA Profiling Core at Baylor College of Medicine
R01 AI120989NIH-National Institute of Allergy and Infectious Diseases grants
R01AI067946NIH-National Institute of Allergy and Infectious Diseases grants
U54HG006542NIH (National Human Genome Research Institute/National Heart, Lung, and Blood Institute)