Publication Date
12-8-2022
Journal
JCI Insight
DOI
10.1172/jci.insight.155481
PMID
36477361
PMCID
PMC9746917
PubMedCentral® Posted Date
12-8-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Humans, Mice, DNA-Binding Proteins, Killer Cells, Natural, Transcription Factors, Innate immunity, Monogenic diseases, NK cells, Cell Biology, Immunology
Abstract
NK cell deficiencies (NKD) are a type of primary immune deficiency in which the major immunologic abnormality affects NK cell number, maturity, or function. Since NK cells contribute to immune defense against virally infected cells, patients with NKD experience higher susceptibility to chronic, recurrent, and fatal viral infections. An individual with recurrent viral infections and mild hypogammaglobulinemia was identified to have an X-linked damaging variant in the transcription factor gene ELF4. The variant does not decrease expression but disrupts ELF4 protein interactions and DNA binding, reducing transcriptional activation of target genes and selectively impairing ELF4 function. Corroborating previous murine models of ELF4 deficiency (Elf4-/-) and using a knockdown human NK cell line, we determined that ELF4 is necessary for normal NK cell development, terminal maturation, and function. Through characterization of the NK cells of the proband, expression of the proband's variant in Elf4-/- mouse hematopoietic precursor cells, and a human in vitro NK cell maturation model, we established this ELF4 variant as a potentially novel cause of NKD.
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Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Diseases Commons, Medical Cell Biology Commons, Medical Immunology Commons, Medical Specialties Commons
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