Mace, EM, Bigley, V, Gunesch, JT et al. (30 more authors) (2017) Biallelic mutations in IRF8 impair human NK cell maturation and function. Journal of Clinical Investigation, 127 (1). pp. 306-320. ISSN 0021-9738
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2017, American Society for Clinical Investigation. Users are allowed to read, download, copy, distribute, print, search, or link to the full texts of Journal of Clinical Investigation articles under the "fair use" limitations of US copyright law. Reproduced in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Haematology (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Institute of Rheumatology & Musculoskeletal Medicine (LIRMM) (Leeds) |
Funding Information: | Funder Grant number Cancer Research UK C7845/A17723 |
Depositing User: | Symplectic Publications |
Date Deposited: | 01 Dec 2016 10:58 |
Last Modified: | 27 Apr 2020 15:18 |
Published Version: | https://doi.org/10.1172/JCI86276 |
Status: | Published |
Publisher: | American Society for Clinical Investigation |
Identification Number: | 10.1172/JCI86276 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:108800 |