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The Science sub-journal Gao Daxing's team at the University of Science and Technology of China showed that cGAS signals drive a special lymphoid tissue structure, which is the basis of autoimmune tissue pathology!

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Aberrant activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase interferon gene stimulator (cGAS-STING) pathway leads to autoimmunity in humans and mice. However, the exact mechanisms by which cGAS-STING pathways initiate adaptive immunity and histopathology are not fully understood.

On August 2, 2024, the Gao Daxing team of the University of Science and Technology of ChinaScience Immunology（IF=17.6）Published online entitled“cGAS-activated endothelial cell–T cell cross-talk initiates tertiary lymphoid structure formation”The research paper,The study showedcGAS-activated endothelial cell-T cell crosstalk initiates the formation of tertiary lymphoid structures.

Here, the researchers used a cGAS knock-in protein (KI) mouse model, which generates systemic autoimmunity. In the lungs of cGAS-KI mice, blood vessels are surrounded by organized lymphoid tissues similar to tertiary lymphoid tissues (TLSs). Cell endogenous cGAS induction can promote CD8⁺Upregulation of CCR5 in T cells and leads to the production of CCL5 in vascular endothelial cells. Peripheral CD8⁺T cells are recruited to the lungs and produce CXCL13 and interferon-gamma. The latter triggers endothelial cell death and enhances the production of CCL5, which is essential for the establishment of TLS. block CCL5 or CCR5, or deplete CD8⁺T cells, disrupting the formation of TLS. cGAS-mediated TLS formation also enhances humoral and antitumor responses.These data suggest that cGAS signaling drives a specialized lymphoid tissue architecture that underlies autoimmune tissue pathology.

Cyclic guanosine monophosphate (GMP) -adenosine monophosphate (AMP) synthase (cGAS) is a cytoplasmic DNA sensor that initiates antiviral immunity. After binding to double-stranded DNA (dsDNA) in a sequence-independent manner, cGAS synthesizes cyclic GMP-AMP (cGAMP), which activates the interferon (IFN) gene stimulating factor (STING), which in turn activates the interferon (IFN) gene. The downstream type I IFN (IFN-I) signal is activated. cGAS-STING pathways play a crucial role in detecting pathogens that use DNA as genetic material.

Exposure of cGAS to self-DNA can lead to adverse immune responses. Deficiency of deoxyribonucleases (DNases), such as cytosolic DNase, TREX1, lysosomal DNase, and DNase II, can lead to severe autoimmune diseases associated with IFN-I, hence the name type I interferon disease.TREX1^−/−In mice that mimic human Aicardi-Goutières syndrome (AGS; a type I interferon disease),cGAS activation in antigen-presenting cells (APCs) promotes an adaptive response, leading to antibody-dependent and T-cell-dependent autoimmunity. Knockout of cGAS or STING reversed the lethality of DNA-deficient mice, suggesting that cGAS recognizes its own DNA and exacerbates the disease. In addition, STING gain-of-function (GOF) mutations have been characterized in infancy-onset STING-associated vasculopathy (SAVI) patients who exhibit pulmonary and vascular inflammation distinct from AGS.Mice carrying the patient-derived STING- GOF mutation exhibit a similar stratified phenotype. In addition, mutations in Coat protein subunit alpha (COPA), which is involved in intracellular transport of STING, can lead to COPA syndrome with STING-dependent inflammatory lung disease.

Although mutations in TREX1, STING, and COPA all resulted in aberrant activation of the cGAS-STING pathway, the phenotypes of these mice varied, suggesting the complexity of cGAS-STING overactivation in vivo. For example, Trex1^−/−Mice are different STING-GOF mice cannot be rescued by IFN-I blockade, suggesting that the underlying mechanisms involved in these two disease conditions are different. However, inTrex1^−/−、STING GOF和Cup^E241K/A higher proportion of activated T cells and IFN-γ-producing T cells were observed in both mice .

In summary, cGAS initiates the formation of TLS through chemokine-mediated crosstalk between endothelial cells and T cells. This mechanism underscores the critical role of innate immune sensors in regulating the adaptive immune response. It provides valuable insights into potential therapeutic strategies for autoimmune diseases and offers a promising avenue for enhancing cancer immunotherapy.

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