γδ T cell-stromal networks modulate matrix composition and vascularity in foreign body response

Area of Science:

• Immunology
• Cell Biology
• Tissue Engineering

Background:

• Tissue fibrosis involves complex immune-stromal interactions, characterized by abnormal extracellular matrix (ECM) deposition and aberrant vasculature.
• The role of specific immune cell subsets, like gamma delta (γδ) T cells, in modulating stromal cell behavior during fibrosis remains incompletely understood.

Purpose of the Study:

• To investigate the role of γδ T cell subsets in shaping fibrosis within the foreign body response using a murine biomaterial implant model.
• To elucidate the mechanisms by which γδ T cells interact with stromal cells (fibroblasts and endothelial cells) to regulate ECM production and vascular development.

Main Methods:

• Analysis of γδ T cell subsets (γδIFNγ and γδ17) at implant sites during the foreign body response.
• Co-culture experiments of fibroblasts with γδ17 cells to assess gene expression.
• Intercellular communication inference analysis to link γδ T cell signaling to stromal cell programs.
• Genetic deletion of γδ T cells in mice to evaluate their impact on fibrotic matrix composition and vascularity.

Main Results:

• Both γδIFNγ and γδ17 γδ T cell subsets accumulate during acute inflammation, with γδ17 cells persisting as major interleukin-17 producers as fibrosis progresses.
• The γδ17 cell population expands with aging and high-fat diet, conditions linked to chronic inflammation and fibrosis.
• γδ17 cell co-culture induced increased collagen gene expression in fibroblasts, and inferred communication pathways linked γδ T cell ligands to ECM remodeling and vascular development in fibroblasts and endothelial cells.
• Genetic ablation of γδ T cells altered ECM component expression and increased vessel size within the fibrotic matrix.

Conclusions:

• γδ T cells, particularly the persistent γδ17 subset, play a significant role in regulating stromal cell behavior during tissue fibrosis.
• These interactions modulate the composition and vascularity of fibrotic tissues, highlighting γδ T cells as potential therapeutic targets for fibrotic diseases.