SRA

We previously reported that X-Box Binding Protein 1 (Xbp1s), an essential transcriptional factor downstream of IL-15 and Akt signaling, controls cell survival and effector function in human natural killer (NK) cells. However, the mechanisms by which Xbp1s regulates NK cell survival and function remains unknown. In this study, by using Xbp1s conditional knock-out (KO) mice, we found that Xbp1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanically, Xbp1s regulates homeostatic NK cell survival through targeting Pim2, a critical anti-apoptotic gene. Pim2 in turn stabilizes Xbp1s protein through phosphorylation at Thr58. Xbp1s enhances NK cell effector function and anti-tumor immunity via recruitment of Tbet to the promoter region of Ifng. Collectively, our findings reveal an important role of IL-15–Xbp1s signaling in NK cell survival and effector function. Overall design: Total RNA was isolated from purified splenic NK cells from IL-15Tg-WT and IL-15Tg-Xbp1s cKO mice using a RNeasy Mini Kit (QIAGEN). The RNA libraries were generated using the KAPA Hyper Prep Kit (KAPA Biosystems). Sequencing was performed on the HiSeq2500.