title: 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.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Mace
authors.forename: Venetia
authors.initials: V
authors.lastname: Bigley
authors.forename: Justin T
authors.initials: JT
authors.lastname: Gunesch
authors.forename: Ivan K
authors.initials: IK
authors.lastname: Chinn
authors.forename: Laura S
authors.initials: LS
authors.lastname: Angelo
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Care
authors.forename: Sheetal
authors.initials: S
authors.lastname: Maisuria
authors.forename: Michael D
authors.initials: MD
authors.lastname: Keller
authors.forename: Sumihito
authors.initials: S
authors.lastname: Togi
authors.forename: Levi B
authors.initials: LB
authors.lastname: Watkin
authors.forename: David F
authors.initials: DF
authors.lastname: LaRosa
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Coban Akdemir
authors.forename: Jansen B
authors.initials: JB
authors.lastname: Smith
authors.forename: Mayra
authors.initials: M
authors.lastname: Hernández-Sanabria
authors.forename: Duy T
authors.initials: DT
authors.lastname: Le
authors.forename: Graham D
authors.initials: GD
authors.lastname: Hogg
authors.forename: Tram N
authors.initials: TN
authors.lastname: Cao
authors.forename: Aharon G
authors.initials: AG
authors.lastname: Freud
authors.forename: Eva P
authors.initials: EP
authors.lastname: Szymanski
authors.forename: Sinisa
authors.initials: S
authors.lastname: Savic
authors.forename: Matthew
authors.initials: M
authors.lastname: Collin
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Cant
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri
authors.forename: Keiko
authors.initials: K
authors.lastname: Ozato
authors.forename: Silke
authors.initials: S
authors.lastname: Paust
authors.forename: Gina M
authors.initials: GM
authors.lastname: Doody
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Orange
mesh_terms: D000483:Alleles; D000818:Animals; D019002:CD56 Antigen / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology; D000099185:Interferon Regulatory Factor-8
chemical_list: D019002:CD56 Antigen; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; C522918:NCAM1 protein, human