Sustained innate interferon is an essential inducer of tertiary lymphoid structures

Area of Science:

• Immunology
• Cell Biology
• Pathology

Background:

• Tertiary lymphoid structures (TLS) mimic secondary lymphoid organs and form in non-lymphoid tissues during inflammation and cancer.
• The specific cell types and signaling pathways driving TLS development remain largely unknown.
• Understanding TLS formation is critical for developing new therapeutic strategies for inflammatory diseases and cancer.

Purpose of the Study:

• To investigate the early cellular and molecular events driving TLS development in the lungs.
• To identify key signaling molecules and cell types essential for TLS formation.
• To elucidate the mechanisms by which type I interferon (IFN-I) influences TLS development.

Main Methods:

• Repeated intranasal instillation of poly(I:C) plus ovalbumin (Ova) in a mouse model.
• Analysis of induced TLS, ranging from aggregates to organized structures with germinal centers.
• Investigated the roles of FAP+ fibroblasts, alveolar macrophages, CCL19, and type I interferon (IFN-I) in TLS development.

Main Results:

• TLS development was independent of FAP+ fibroblasts, alveolar macrophages, and CCL19.
• TLS formation critically depended on type I interferon (IFN-I).
• IFN-I initiated two synergistic pathways: LTα induction for CXCL13 production via LTβR, and direct stromal cell sensing for T-cell chemokine production (CXCL9, CXCL10, CCL19, CCL21).

Conclusions:

• Sustained type I interferon (IFN-I) production, alongside antigen presence, is essential for inducing functional TLS in the lungs.
• IFN-I orchestrates distinct signaling cascades involving lymphoid and stromal cells to drive TLS formation.
• The findings provide crucial insights into the immunobiology of TLS and potential therapeutic targets.