The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33–ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33–ST2 axis in infections and inflammatory diseases.

多效性警报素白细胞介素 33 (IL-33) 通过其受体 ST2 驱动 1 型、2 型和调节性 T 细胞反应。 ST2 表达强度和动态的子集特异性差异表明，转录调控是协调 T 细胞免疫中 IL-33-ST2 信号传导的背景依赖性活动的关键。在这里，我们在小鼠和人类中发现了一个以前未被识别的替代启动子，它位于精心设计的 ST2 编码基因的上游，并在 1 型免疫中驱动 ST2 表达。缺乏该启动子的小鼠在 1 型偏向性 T 细胞中选择性丧失 ST2 表达，但在 2 型偏向性 T 细胞中则不然，导致病毒感染后细胞毒性 T 细胞 (CTL) 和 T 辅助 1 细胞的扩增受损。通过 1 型启动子驱动的 ST2 产生的 T 细胞内在 IL-33 信号传导对于产生克隆多样化的抗病毒短寿命效应 CTL 群体至关重要。因此，谱系特异性替代启动子的使用可指导 T 细胞亚群中的警报素反应，并为感染和炎症性疾病中免疫细胞特异性靶向 IL-33-ST2 轴提供机会。