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Immunity. 2018 Jun 19;48(6):1172-1182.e6. doi: 10.1016/j.immuni.2018.04.018. Epub 2018 May 29.

Transcription Factor IRF8 Orchestrates the Adaptive Natural Killer Cell Response.

Author information

1
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
2
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: sunj@mskcc.org.

Abstract

Natural killer (NK) cells are innate lymphocytes that display features of adaptive immunity during viral infection. Biallelic mutations in IRF8 have been reported to cause familial NK cell deficiency and susceptibility to severe viral infection in humans; however, the precise role of this transcription factor in regulating NK cell function remains unknown. Here, we show that cell-intrinsic IRF8 was required for NK-cell-mediated protection against mouse cytomegalovirus infection. During viral exposure, NK cells upregulated IRF8 through interleukin-12 (IL-12) signaling and the transcription factor STAT4, which promoted epigenetic remodeling of the Irf8 locus. Moreover, IRF8 facilitated the proliferative burst of virus-specific NK cells by promoting expression of cell-cycle genes and directly controlling Zbtb32, a master regulator of virus-driven NK cell proliferation. These findings identify the function and cell-type-specific regulation of IRF8 in NK-cell-mediated antiviral immunity and provide a mechanistic understanding of viral susceptibility in patients with IRF8 mutations.

KEYWORDS:

IRF8; MCMV; NK cells; transcriptional regulation; viral infection

PMID:
29858012
PMCID:
PMC6233715
[Available on 2019-06-19]
DOI:
10.1016/j.immuni.2018.04.018
[Indexed for MEDLINE]

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