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J Clin Invest. 2017 Jan 3;127(1):306-320. doi: 10.1172/JCI86276. Epub 2016 Nov 28.

Biallelic mutations in IRF8 impair human NK cell maturation and function.

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.

PMID:
27893462
PMCID:
PMC5199714
DOI:
10.1172/JCI86276
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

J.R.Lupski has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, has stock options in Lasergen, Inc. is a member of the Scientific Advisory Board of Baylor Genetics, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting (5294533; 5306616; 5523217; 5599920; 5667968; 5780223; 6132954; 6713300; 7141420; 7189511; 7192579; 7273698; 7537899; 8129353; 9365899; 0424473; 0610396; 0989805). The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (CMA) and clinical exome sequencing offered in Baylor Genetics (BMGL: http://www.bmgl.com/BMGL/Default.aspx).

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