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.

T细胞产生的组织警报蛋白白介素（IL）-15和干扰素β（IFNβ）以及IL-21对导致乳糜泻中组织破坏的细胞毒性T淋巴细胞（CTL）重编程的各自作用了解得很少。初级肠道CTL的转录组学和表观遗传学分析显示，对组织警报蛋白的反应存在大量明显的时间转录变化，而IL-21的影响是有限的。尽管在动力学和强度上有所不同，但仅对三种刺激均诱导了抗病毒途径。此外，基因表达的变化主要独立于H3K27ac的变化，表明其他调控机制可驱动强大的转录反应。最后，我们发现IL-15 /IFNβ/ IL-21的转录特征可能与复杂免疫疾病风险基因座的转录改变有关。这些结果共同提供了对分子机制的新见解，这些分子机制在模拟自身免疫性疾病患者的炎性环境的条件下促进了CTL的活化。