Abstract：
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.
摘要：
环磷酸鸟苷-磷酸腺苷合成酶-干扰素基因刺激因子（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途径启动适应性免疫和组织病理学的确切机制尚不完全清楚。这里,我们使用了cGAS敲入（KI）小鼠模型，该模型可产生全身性自身免疫。在cGAS-KI小鼠的肺中，血管由类似三级淋巴结构（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。将外周CD8+T细胞募集至肺并产生CXCL13和干扰素-γ。后者引发内皮细胞死亡，加强CCL5生产，并且对于TLS的建立至关重要。阻断CCL5或CCR5，或消耗CD8+T细胞，TLS形成受损。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信号传导驱动作为自身免疫组织病理学基础的专门淋巴结构。
