Upon viral infection, stressed or damaged cells can release alarmins like IL‐33 that act as endogenous danger signals alerting innate and adaptive immune cells. IL‐33 coming from nonhematopoietic cells has been identified as important factor triggering the expansion of antiviral CD8⁺ T cells. In LN the critical cellular source of IL‐33 is unknown, as is its potential cell‐intrinsic function as a chromatin‐associated factor. Using IL‐33‐GFP reporter mice, we identify fibroblastic reticular cells (FRC) and lymphatic endothelial cells (LEC) as the main IL‐33 source. In homeostasis, IL‐33 is dispensable as a transcriptional regulator in FRC, indicating it functions mainly as released cytokine. Early during infection with lymphocytic choriomeningitis virus (LCMV) clone 13, both FRC and LEC lose IL‐33 protein expression suggesting cytokine release, correlating timewise with IL‐33 receptor expression by reactive CD8⁺ T cells and their greatly augmented expansion in WT versus ll33^−/− mice. Using mice lacking IL‐33 selectively in FRC versus LEC, we identify FRC as key IL‐33 source driving acute and chronic antiviral T‐cell responses. Collectively, these findings show that LN T‐zone FRC not only regulate the homeostasis of naïve T cells but also their expansion and differentiation several days into an antiviral response.

中文翻译：

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成纤维细胞衍生的IL-33可用于淋巴结稳态，但对于CD8 T细胞对急性和慢性病毒感染的反应至关重要。

受到病毒感染后，压力过大或受损的细胞会释放出警报蛋白（如IL-33），作为内源性危险信号，提醒先天和适应性免疫细胞。来自非造血细胞的IL-33已被确定为触发抗病毒CD8 ⁺扩增的重要因素T细胞。在LN中，IL-33的关键细胞来源是未知的，它作为染色质相关因子的潜在细胞内在功能也是未知的。使用IL-33-GFP报告基因小鼠，我们确定了成纤维细胞网状细胞（FRC）和淋巴管内皮细胞（LEC）是主要的IL-33来源。在体内平衡中，IL‐33可作为FRC中的转录调节剂，这表明它主要用作释放的细胞因子。在感染淋巴细胞性脉络膜脑膜炎病毒（LCMV）克隆13的早期，FRC和LEC均失去IL-33蛋白表达，提示细胞因子释放，与反应性CD8 ⁺ T细胞的IL-33受体表达及时相关，并且它们在WT和ll33中的扩增大大增强^-/-老鼠。使用在FRC与LEC中选择性缺乏IL-33的小鼠，我们确定FRC是驱动急性和慢性抗病毒T细胞反应的重要IL-33来源。总的来说，这些发现表明LN T区FRC不仅调节幼稚T细胞的稳态，而且还可以在几天内扩展和分化为抗病毒反应。