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

TitleBiallelic mutations in IRF8 impair human NK cell maturation and function.
Publication TypeJournal Article
Year of Publication2017
AuthorsMace, 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, ZCoban, Smith, JB, Hernández-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
JournalJ Clin Invest
Date Published2017 01 03
KeywordsAlleles, Animals, CD56 Antigen, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Interferon Regulatory Factors, Killer Cells, Natural, Male, Mice, Mice, Knockout, Mutation, Virus Diseases

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.

Alternate JournalJ. Clin. Invest.
PubMed ID27893462
PubMed Central IDPMC5199714
Grant ListR01 AI067946 / AI / NIAID NIH HHS / United States
R01 AI120989 / AI / NIAID NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States