Spliced X-box–binding protein 1 (XBP1s) is an essential transcription factor downstream of interleukin-15 (IL-15) and AKT signaling, which controls cell survival and effector functions of human natural killer (NK) cells. However, the precise mechanisms, especially the downstream targets of XBP1s, remain unknown. In this study, by using XBP1 conditional knockout 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 by targeting PIM-2, a critical anti-apoptotic gene, which in turn stabilizes XBP1s protein by phosphorylating it at Thr 58 . In addition, XBP1s enhances the effector functions and antitumor 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.

中文翻译：

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XBP1s–PIM-2 正反馈回路控制 IL-15 介导的自然杀伤细胞存活

剪接的 X-box 结合蛋白 1 (XBP1s) 是白细胞介素 15 (IL-15) 和 AKT 信号下游的重要转录因子，它控制人类自然杀伤 (NK) 细胞的细胞存活和效应功能。然而，确切的机制，尤其是 XBP1 的下游目标，仍然未知。在这项研究中，通过使用 XBP1 条件性基因敲除小鼠，我们发现 XBP1s 对 IL-15 介导的 NK 细胞存活至关重要，但对体外和体内增殖没有影响。从机制上讲，XBP1s 通过靶向 PIM-2 来调节稳态 NK 细胞存活，PIM-2 是一种关键的抗凋亡基因，它反过来通过在 Thr 磷酸化 XBP1s 蛋白来稳定它58. 此外，XBP1s 通过将 T-bet 募集到 NK 细胞的启动子区域来增强 NK 细胞的效应功能和抗肿瘤免疫。Ifng. 总的来说，我们的研究结果确定了一种以前未知的机制，IL-15-XBP1s 信号通过该机制调节 NK 细胞的存活和效应功能。