AUTHOR=Meissl Katrin , Simonović Natalija , Amenitsch Lena , Witalisz-Siepracka Agnieszka , Klein Klara , Lassnig Caroline , Puga Ana , Vogl Claus , Poelzl Andrea , Bosmann Markus , Dohnal Alexander , Sexl Veronika , Müller Mathias , Strobl Birgit 

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

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.02189

DOI=10.3389/fimmu.2020.02189

ISSN=1664-3224

ABSTRACT=<p>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 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 STAT1α (<italic>Stat1</italic><sup>α/α</sup>) or the STAT1β (<italic>Stat1<sup>β</sup><sup>/</sup><sup>β</sup></italic>) isoform. NK cells from <italic>Stat1</italic><sup>α/α</sup> mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from <italic>Stat1</italic><sup>β/β</sup> mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack STAT1 (<italic>Stat1<sup>–/–</sup></italic>). Mechanistically, we show that NK cell maturation requires the presence of STAT1α in the niche rather than in NK cells themselves and that NK cell maturation depends on IFNγ signaling under homeostatic conditions. The impaired NK cell maturation in <italic>Stat1</italic><sup>β/β</sup> mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of <italic>Stat1</italic><sup>β/β</sup> mice with exogenous IL-15/IL-15Rα 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 STAT1α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.</p>