Aberrant activation of the cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes (cGAS-STING) pathway causes autoimmunity in humans and mice; however, the exact mechanism by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology is still not fully understood. Here, we used a cGAS knockin (KI) mouse model that develops systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels were enclosed by organized lymphoid tissues that resemble tertiary lymphoid structures (TLSs). Cell-intrinsic cGAS induction promoted up-regulation of CCR5 in CD8 + T cells and led to CCL5 production in vascular endothelial cells. Peripheral CD8 + T cells were recruited to the lungs and produced CXCL13 and interferon-γ. The latter triggered endothelial cell death, potentiated CCL5 production, and was essential for TLS establishment. Blocking CCL5 or CCR5, or depleting CD8 + T cells, impaired TLS formation. cGAS-mediated TLS formation also enhanced humoral and antitumor responses. These data demonstrate that cGAS signaling drives a specialized lymphoid structure that underlies autoimmune tissue pathology.

中文翻译：

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cGAS激活的内皮细胞-T细胞串扰启动三级淋巴结构形成


环磷酸鸟苷-磷酸腺苷合酶-干扰素基因刺激剂 (cGAS-STING) 通路的异常激活会导致人和小鼠的自身免疫；然而，cGAS-STING 通路启动适应性免疫和组织病理学的确切机制仍不完全清楚。在这里，我们使用了可产生系统性自身免疫的 cGAS 敲入 (KI) 小鼠模型。在 cGAS-KI 小鼠的肺部，血管被类似于三级淋巴结构 (TLS) 的有组织的淋巴组织包围。细胞固有的 cGAS 诱导促进 CD8 + T 细胞中 CCR5 的上调，并导致血管内皮细胞中 CCL5 的产生。外周 CD8 + T 细胞被募集到肺部并产生 CXCL13 和干扰素-γ。后者触发内皮细胞死亡，增强 CCL5 的产生，并且对于 TLS 的建立至关重要。阻断 CCL5 或 CCR5，或耗尽 CD8 + T 细胞，会损害 TLS 的形成。 cGAS 介导的 TLS 形成也增强了体液和抗肿瘤反应。这些数据表明，cGAS 信号传导驱动一种特殊的淋巴结构，该结构是自身免疫组织病理学的基础。