An ELF4 hypomorphic variant results in NK cell deficiency

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.

The transcription factor ELF4 alleviates inflammatory bowel disease by activating IL1RN transcription, suppressing inflammatory TH17 cell activity, and inducing macrophage M2 polarization

“…In mouse macrophages, ELF4 restricts the upregulation of the inflammasome by maintaining the expression of anti-inflammatory genes such as IL1RN (8). Macrophages with ELF4 gene knockout cannot maintain the transcription of the critical anti-inflammatory gene IL1RN but up-regulate pro-inflammatory genes, amplifying the inflammatory response (38).…”

“…ELF4 plays a vital role in innate and adaptive immune cells in the immune system. ELF4 deficiency in the embryonic stage may lead to reduced cytotoxicity of NK cells, increased activity of TH17 cells, and abnormal proliferation and transportation of CD8+ T cells (38). In addition, stable-state mice with ELF4 gene deficiency have reduced secretion of IL1RN factor in their blood, increased Th17 cells in their innate layer, and increased Th17 cells in their lymph nodes (8,41).…”