cGAS-activated endothelial cell-T cell cross-talk initiates tertiary lymphoid structure formation

Area of Science:

• Immunology
• Molecular Biology
• Pathology

Background:

• Aberrant activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is linked to human and mouse autoimmunity.
• The precise mechanisms by which the cGAS-STING pathway initiates adaptive immunity and tissue pathology remain incompletely understood.

Purpose of the Study:

• To investigate the role of cGAS-STING pathway activation in driving autoimmune responses and tissue pathology.
• To elucidate the mechanisms by which cGAS signaling promotes the formation of organized lymphoid structures in autoimmune conditions.

Main Methods:

• Utilized a cGAS knockin (KI) mouse model exhibiting systemic autoimmunity.
• Analyzed lung tissues to identify lymphoid structures and characterize immune cell populations and molecular signaling.
• Investigated the roles of CD8+ T cells, CCL5, and CCR5 in tertiary lymphoid structure (TLS) formation through blocking and depletion strategies.

Main Results:

• cGAS-KI mice developed systemic autoimmunity with organized lymphoid tissues resembling tertiary lymphoid structures (TLSs) enclosing lung blood vessels.
• Cell-intrinsic cGAS induction upregulated CCR5 in CD8+ T cells and induced CCL5 production in vascular endothelial cells.
• Recruited peripheral CD8+ T cells produced CXCL13 and interferon-γ, which triggered endothelial cell death, enhanced CCL5 production, and were crucial for TLS establishment.
• Blocking CCL5 or CCR5, or depleting CD8+ T cells, significantly impaired TLS formation.
• cGAS-mediated TLS formation was also found to enhance humoral and antitumor immune responses.

Conclusions:

• cGAS signaling is a key driver of specialized lymphoid structure formation that underlies autoimmune tissue pathology.
• The cGAS-STING pathway orchestrates a cascade involving CD8+ T cell recruitment and activation, leading to TLS development and contributing to autoimmune disease.
• Targeting cGAS-STING pathway components or downstream mediators like CCL5/CCR5 could offer therapeutic strategies for autoimmune diseases.