Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL...

Area of Science:

• Immunology
• Cell Biology
• Inflammation Research

Background:

• Tertiary lymphoid structures (TLS) are aggregates of lymphocytes found at sites of chronic inflammation.
• Immunofibroblasts are cells within TLS implicated in regulating lymphocyte aggregation.

Purpose of the Study:

• To elucidate the immunoregulatory function of immunofibroblasts in TLS formation.
• To investigate the role of inducible T-cell co-stimulator ligand (ICOS/ICOS-L) in this process.

Main Methods:

• Upregulation of ICOSL on immunofibroblasts and dendritic cells (DCs) during inflammation.
• Interaction of ICOSL with ICOS+ T cells to induce LTα3 production.
• Analysis of chemokine production and TLS assembly via TNF receptor I/II (TNFRI/II) engagement.
• Pharmacological and genetic blockade of ICOS/ICOS-L interaction.

Main Results:

• Immunofibroblasts, via ICOSL, bind ICOS+ T cells, inducing LTα3 production.
• LTα3 drives chemokine production essential for TLS assembly through TNFRI/II signaling.
• Blocking ICOS/ICOS-L interaction impairs LTα expression, chemokine production, and TLS formation.

Conclusions:

• A novel immunoregulatory function for immunofibroblasts involving ICOS/ICOS-L interaction is identified.
• LTα3 is revealed as a key regulator and potential biomarker for TLS formation and maintenance.
• The ICOS/ICOS-L pathway is critical for initiating TLS assembly in chronic inflammation.