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 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 (Stat1α/α) or the STAT1β (Stat1β/β) isoform. NK cells from Stat1α/α mice matured normally and controlled transplanted tumor cells as efficiently as NK cells from wild-type mice. In contrast, NK cells from Stat1β/β 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 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 Stat1β/β mice was paralleled by decreased IL-15 receptor alpha (IL-15Rα) surface levels on dendritic cells, macrophages and monocytes. Treatment of Stat1β/β 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.
Highlights
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is employed by many different cytokines and regulates diverse cellular processes, such as differentiation, proliferation, and survival [1]
Studies in gene-modified mice challenged this concept by demonstrating that STAT1β, STAT3β, and STAT4β are capable of inducing gene expression that quantitatively and qualitatively differs from transcriptional responses induced by the respective α-isoform [13,14,15,16]
Using mixed bone marrow chimera experiments we show that STAT1α in the environment rather than in natural killer (NK) cells themselves is required for full NK cell maturation in the spleen, which is consistent with findings in mice lacking both Signal transducer and activator of transcription 1 (STAT1) isoforms [11]
Summary
The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is employed by many different cytokines and regulates diverse cellular processes, such as differentiation, proliferation, and survival [1]. Studies in gene-modified mice challenged this concept by demonstrating that STAT1β, STAT3β, and STAT4β are capable of inducing gene expression that quantitatively and qualitatively differs from transcriptional responses induced by the respective α-isoform [13,14,15,16]. Splicing patterns are profoundly altered in cancer cells and evidence has accumulated that targeting the splicing machinery might be a promising strategy for cancer therapy [19,20,21]. It is unknown how splicing of STAT1, STAT3, and STAT4 is regulated. The impact of STAT1 isoforms on tumor surveillance is unknown
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