Journal
CELL REPORTS
Volume 24, Issue 8, Pages 1949-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.07.060
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Funding
- NIH National Institute of General Medical Sciences [T32GM007739]
- NIH National Institute of Allergy and Infectious Diseases [F30 AI136239]
- NIH [CA009149, U01 HG007893, AI100874, AI130043, P30CA008748]
- Novo Nordisk Foundation
- Ludwig Center for Cancer Immunotherapy
- American Cancer Society
- Burroughs Wellcome Fund
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Natural killer (NK) cells are innate lymphocytes that possess adaptive features, including antigen-specific clonal expansion and long-lived memory responses. Although previous work demonstrated that type I interferon (IFN) signaling is crucial for NK cell expansion and memory cell formation following mouse cytomegalovirus (MCMV) infection, the global transcriptional mechanisms underlying type I IFN-mediated responses remained to be determined. Here, we demonstrate that among the suite of transcripts induced in activated NK cells, IFN-alpha is necessary and sufficient to promote expression of its downstream transcription factors STAT1, STAT2, and IRF9, via an auto-regulatory, feedforward loop. Similar to STAT1 deficiency, we show that STAT2- or IRF9-deficient NK cells are defective in their ability to expand following MCMV infection, in part because of diminished survival rather than an inability to proliferate. Thus, our findings demonstrate that individual ISGF3 components are crucial cell-autonomous and non-redundant regulators of the NK cell response to viral infection.
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