Cutting Edge: STAT4 promotes Bhlhe40 induction to drive protective IFN-γ from natural killer cells during viral infection

NK cells represent a cellular component of the mammalian innate immune system, and mount rapid responses against viral infection, including the secretion of the potent anti-viral effector cytokine IFN-γ. Following mouse cytomegalovirus (MCMV) infection, Bhlhe40 was the most highly induced transcript...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2023-11, Vol.211 (10), p.1469-1474
Main Authors: Kim, Hyunu, Abbasi, Aamna, Sharrock, Jessica, Santosa, Endi K., Lau, Colleen M., Edelson, Brian T., Sun, Joseph C.
Format: Article
Language:English
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Summary:NK cells represent a cellular component of the mammalian innate immune system, and mount rapid responses against viral infection, including the secretion of the potent anti-viral effector cytokine IFN-γ. Following mouse cytomegalovirus (MCMV) infection, Bhlhe40 was the most highly induced transcription factor in NK cells among the basic helix-loop-helix family. Bhlhe40 upregulation in NK cells depended upon IL-12 and IL-18 signals, with the promoter of Bhlhe40 enriched for STAT4 and the permissive histone H3K4me3, and STAT4-deficient NK cells showing an impairment of Bhlhe40 induction and diminished H3K4me3. Transcriptomic and protein analysis of Bhlhe40-deficient NK cells revealed a defect in IFN-γ production during MCMV infection, resulting in diminished protective immunity following viral challenge. Finally, we provide evidence that Bhlhe40 directly promotes IFN-γ by binding throughout the Ifng loci in activated NK cells. Thus, our study reveals how STAT4-mediated control of Bhlhe40 drives protective IFN-γ secretion by NK cells during viral infection.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.2300402