Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Department of Medicine, University of Chicago, Chicago, USA; Committee on Immunology, University of Chicago, Chicago, USA.
J Autoimmun. 2020 Mar;108:102422. doi: 10.1016/j.jaut.2020.102422. Epub 2020 Feb 4.
The respective effects of tissue alarmins interleukin (IL)-15 and interferon beta (IFNβ), and IL-21 produced by T cells on the reprogramming of cytotoxic T lymphocytes (CTLs) that cause tissue destruction in celiac disease is poorly understood. Transcriptomic and epigenetic profiling of primary intestinal CTLs showed massive and distinct temporal transcriptional changes in response to tissue alarmins, while the impact of IL-21 was limited. Only anti-viral pathways were induced in response to all the three stimuli, albeit with differences in dynamics and strength. Moreover, changes in gene expression were primarily independent of changes in H3K27ac, suggesting that other regulatory mechanisms drive the robust transcriptional response. Finally, we found that IL-15/IFNβ/IL-21 transcriptional signatures could be linked to transcriptional alterations in risk loci for complex immune diseases. Together these results provide new insights into molecular mechanisms that fuel the activation of CTLs under conditions that emulate the inflammatory environment in patients with autoimmune diseases.
细胞危险信号白细胞介素 (IL)-15 和干扰素β (IFNβ) 以及 T 细胞产生的白细胞介素 21 对引起乳糜泻组织破坏的细胞毒性 T 淋巴细胞 (CTL) 重编程的各自影响知之甚少。对原发性肠道 CTL 的转录组和表观遗传谱分析显示，细胞危险信号会引起大量且明显的时间转录变化，而白细胞介素 21 的影响有限。仅抗病毒途径会响应所有这三种刺激，但在动力学和强度上存在差异。此外，基因表达的变化主要与 H3K27ac 的变化无关，这表明其他调控机制驱动了强大的转录反应。最后，我们发现，IL-15/IFNβ/IL-21 转录特征可能与复杂免疫疾病风险基因座的转录改变相关联。这些结果为在模拟自身免疫性疾病患者炎症环境的条件下激活 CTL 的分子机制提供了新的见解。
