Non-redundant ISGF3 Components Promote NK Cell Survival in an Auto-regulatory Manner during Viral Infection

TY - JOUR

T1 - Non-redundant ISGF3 Components Promote NK Cell Survival in an Auto-regulatory Manner during Viral Infection

AU - Geary, Clair D.

AU - Krishna, Chirag

AU - Lau, Colleen M.

AU - Adams, Nicholas M.

AU - Gearty, Sofia V.

AU - Pritykin, Yuri

AU - Thomsen, Allan R.

AU - Leslie, Christina S.

AU - Sun, Joseph C.

PY - 2018/8/21

Y1 - 2018/8/21

N2 - 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-α 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. Using RNA-seq and ChIP-seq, Geary et al. investigate the impacts of type I interferon on NK cells during MCMV infection and demonstrate crucial and non-redundant roles for STAT1, STAT2, and IRF9 in promoting cytotoxicity and survival of antiviral NK cells.

AB - 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-α 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. Using RNA-seq and ChIP-seq, Geary et al. investigate the impacts of type I interferon on NK cells during MCMV infection and demonstrate crucial and non-redundant roles for STAT1, STAT2, and IRF9 in promoting cytotoxicity and survival of antiviral NK cells.

KW - interferon

KW - IRF9

KW - MCMV

KW - NK cells

KW - STAT2

KW - transcriptional regulation

KW - viral infection

U2 - 10.1016/j.celrep.2018.07.060

DO - 10.1016/j.celrep.2018.07.060

M3 - Journal article

C2 - 30134157

AN - SCOPUS:85051142297

SN - 2639-1856

VL - 24

SP - 1949

EP - 1957

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -