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

Natural killer (NK) cells are important components of the innate immune defense against infections and cancers. Signal transducer and activator of transcription 1 is a transcription factor that is essential for NK cell maturation and NK cell-dependent tumor surveillance. Two alternatively spliced isoforms of exist: a full-length and a C-terminally truncated 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 duanyu18131 splicing, we made use of knock-in mice expressing either only the duanyu18131α (Stat1 ^α/α) or the duanyu18131β (Stat1 ) isoform. NK cells from Stat1 ^α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1 ^β/β mice showed impaired maturation and effector functions, albeit less severe than NK cells from mice that completely lack duanyu18131 (Stat1 ). Mechanistically, we show that NK cell maturation requires the presence of duanyu18131α 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 Stat1 ^β/β mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1 ^β/β mice with exogenous IL-15/IL-15Rα complexes rescued NK cell maturation but not their effector functions. Collectively, our findings provide evidence that duanyu18131 isoforms are not functionally redundant in regulating NK cell activity and that the absence of duanyu18131α severely impairs, but does not abolish, NK cell-dependent tumor surveillance.

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