An XBP1s-PIM-2 positive feedback loop controls IL-15-mediated survival of natural killer cells

We previously reported that XBP1s, an essential transcription factor downstream of IL-15 and AKT signaling, controls cell survival and effector functions of human natural killer (NK) cells. However, the precise mechanisms remain unknown. In this study, by using XBP1 conditional knock-out mice, we found that XBP1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanistically, XBP1s regulates homeostatic NK cell survival through targeting PIM-2, a critical anti-apoptotic gene, which in turn stabilizes XBP1s protein by phosphorylating it at Thr58. In addition, XBP1s enhances the effector functions and anti-tumor immunity of NK cells by recruiting T-bet to the promoter region of Ifng. Collectively, our findings identify a previously unknown mechanism by which IL-15–XBP1s signaling regulates the survival and effector functions of NK cells. 5 × 10E6 purified mouse primary NK cells from Il15TgXbp1f/f mice were pretreated with IL-15 (50 ng/ml) for 1 h. chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-Seq) was performed.