德国柏林自由大学Max Löhning研究组发现，白介素-33 (IL-33)受体基因的1型免疫限制性启动子指导抗病毒T细胞反应。2024年1月3日出版的《自然—免疫学》发表了这项成果。

他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，该启动子位于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型偏倚T细胞中表现出ST2表达的选择性缺失，而不是2型偏倚T细胞，导致细胞毒性T细胞(CTL)和T辅助1细胞在病毒感染时的扩增受损。

T细胞内部的IL-33信号通过1型启动子驱动的ST2是产生抗病毒短期效应CTL克隆多样性的关键。因此，谱系特异性替代启动子的使用指导了T细胞亚群中的警报蛋白反应性，并为感染和炎症性疾病中免疫细胞特异性靶向IL-33-ST2轴提供了机会。

据介绍，多效报警蛋白IL-33通过其受体ST2驱动1型、2型和调节性T细胞反应。ST2表达强度和动态的亚群特异性差异表明，转录调节是协调T细胞免疫中IL-33-ST2信号通路上下文依赖性活性的关键。

附：英文原文

Title: A type 1 immunity-restricted promoter of the IL33 receptor gene directs antiviral T-cell responses

Author: Brunner, Tobias M., Serve, Sebastian, Marx, Anna-Friederike, Fadejeva, Jelizaveta, Saikali, Philippe, Dzamukova, Maria, Durn-Hernndez, Nayar, Kommer, Christoph, Heinrich, Frederik, Durek, Pawel, Heinz, Gitta A., Hfer, Thomas, Mashreghi, Mir-Farzin, Khn, Ralf, Pinschewer, Daniel D., Lhning, Max

Issue&Volume: 2024-01-03

Abstract: 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.

DOI: 10.1038/s41590-023-01697-6

Source: https://www.nature.com/articles/s41590-023-01697-6