Post by Nadica (She/Her) on Aug 5, 2024 8:14:25 GMT
cGAS-activated endothelial cell–T cell cross-talk initiates tertiary lymphoid structure formation - Published Aug 2, 2024
Editor’s summary
Overactivation of the innate immune sensing cGAS-STING pathway can lead to inflammation and autoimmunity. To investigate how cGAS hyperactivation drives lung inflammation, Zhao et al. generated a cGAS conditional knockin mouse model. Hyperactivation of cGAS resulted in the formation of tertiary lymphoid structures (TLSs) in the lung, which enhanced antibody responses and antitumor immunity. CCL5-producing endothelial cells in the lung promoted CD8+ T cell recruitment to TLSs via CCR5 signaling, which was induced by T cell–intrinsic cGAS expression. Blocking CCR5/CCL5 impaired TLS formation, suggesting that CCR5/CCL5 could be targeted therapeutically to treat autoimmunity or to enhance antitumor immunity. —Hannah Isles
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.
Editor’s summary
Overactivation of the innate immune sensing cGAS-STING pathway can lead to inflammation and autoimmunity. To investigate how cGAS hyperactivation drives lung inflammation, Zhao et al. generated a cGAS conditional knockin mouse model. Hyperactivation of cGAS resulted in the formation of tertiary lymphoid structures (TLSs) in the lung, which enhanced antibody responses and antitumor immunity. CCL5-producing endothelial cells in the lung promoted CD8+ T cell recruitment to TLSs via CCR5 signaling, which was induced by T cell–intrinsic cGAS expression. Blocking CCR5/CCL5 impaired TLS formation, suggesting that CCR5/CCL5 could be targeted therapeutically to treat autoimmunity or to enhance antitumor immunity. —Hannah Isles
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.