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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.
For re-use rights please refer to the publisher's terms and conditions.
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.
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
URL: http://dx.doi.org/10.1172/JCI86276
DOI: 10.1172/JCI86276
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