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STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity.

ABSTRACT: Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1? and a C-terminally truncated STAT1? isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with the cellular splicing machinery. To investigate whether NK cell-mediated tumor surveillance is affected by a switch in STAT1 splicing, we made use of knock-in mice expressing either only the STAT1? (Stat1 ?/?) or the STAT1? (Stat1? / ? ) isoform. NK cells from Stat1 ?/? mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1 ?/? mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (Stat1-/- ). Mechanistically, we show that NK cell maturation requires the presence of STAT1? in the niche rather than in NK cells themselves and that NK cell maturation depends on IFN? signaling under homeostatic conditions. The impaired NK cell maturation in Stat1 ?/? mice was paralleled by decreased IL-15 receptor alpha (IL-15R?) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1 ?/? mice with exogenous IL-15/IL-15R? complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that STAT1 isoforms are not functionally redundant in regulating NK cell activity and that the absence of STAT1? severely impairs, but does not abolish, NK cell-dependent tumor surveillance.

SUBMITTER: Meissl K

PROVIDER: S-EPMC7519029 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity.

Meissl Katrin K Simonović Natalija N Amenitsch Lena L Witalisz-Siepracka Agnieszka A Klein Klara K Lassnig Caroline C Puga Ana A Vogl Claus C Poelzl Andrea A Bosmann Markus M Dohnal Alexander A Sexl Veronika V Müller Mathias M Strobl Birgit B

Frontiers in immunology 20200911

Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 (STAT1) is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of STAT1 exist: a full-length STAT1α and a C-terminally truncated STAT1β isoform. Aberrant splicing is frequently observed in cancer cells and several anti-cancer drugs interfere with t ...[more]

PMID: 33042133

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STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity.

Publications

STAT1 Isoforms Differentially Regulate NK Cell Maturation and Anti-tumor Activity.

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