cGAS-activated endothelial cell–T cell cross-talk initiates tertiary lymphoid structure formation
Ruibo Zhao, Jinghe Zhang, Jialu Ma, Yali Qu, Zhenrong Yang, Zhinan Yin, Fengyin Li, Zhongjun Dong, Qinmiao Sun, Shu Zhu, Zhijian J. Chen, Daxing Gao
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.