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

Abstract Immune-stromal crosstalk governs tissue fibrosis, which is marked by dysregulated extracellular matrix (ECM) production and aberrant vasculature. Here, we investigate how γδ T cell interactions with stromal cells shape fibrosis in the foreign body response. During the acute reaction, type-1 (γδIFNγ) and type-17 (γδ17) effector subsets accumulated at the implant. While γδIFNγ decreased as fibrosis progressed, activated γδ17 persisted as dominant interleukin-17 producers. The γδ17 increased with aging and high-fat diet, both factors associated with chronic inflammation and fibrosis. Co-culture with γδ17 stimulated fibroblast expression of collagen genes and intercellular communication inference linked γδ T cell ligands to activation of ECM remodeling and vascular development programs in fibroblasts and endothelial cells. Finally, genetic deletion of γδ T cells altered expression of ECM components and increased vessel size within the fibrotic matrix. Altogether, our findings implicate γδ T cells in regulating stromal behavior to modulate composition and vascularity of fibrotic tissues.