γδ17 T cell-stromal networks modulate matrix composition and vascularity in foreign body response

Ruta, A.; Krishnan, K.; Woo, J.; Mejias, J. C.; Gray-Gaillard, E. F.; Maestas, D. R.; Nguyen, H. H.; Rindone, A. N.; Cherry, C.; Patatanian, M.; Yu, F. H.; Yang, B.; Amelung, C.; King, C. D.; Schilling, B.; Gerecht, S.; Fertig, E. J.; Huyer, L. D.; Pardoll, D. M.; Elisseeff, J. H.

doi:10.1101/2025.09.30.679608

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bioRxiv · 10.1101/2025.09.30.679608

γδ17 T cell-stromal networks modulate matrix composition and vascularity in foreign body response

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Abstract

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

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Ruta, A., Krishnan, K., Woo, J., Mejias, J. C., Gray-Gaillard, E. F., Maestas, D. R., Nguyen, H. H., Rindone, A. N., Cherry, C., Patatanian, M., Yu, F. H., Yang, B., Amelung, C., King, C. D., Schilling, B., Gerecht, S., Fertig, E. J., Huyer, L. D., Pardoll, D. M., Elisseeff, J. H.. 2025-10-02. γδ17 T cell-stromal networks modulate matrix composition and vascularity in foreign body response. https://doi.org/10.1101/2025.09.30.679608

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