Regulatory T cells clonally expand and contribute to stromal cell function in fibrotic response to synthetic implants
Mejias, J. C.; Krishnan, K.; Ruta, A.; Ramanujam, A. S.; Gray-Gaillard, E. F.; Huyer, L. D.; Maestas, D. R.; Nagaraj, S.; Yu, F. H.; Rindone, A. N.; Abraham, P.; Browne, M.; Fertig, E. J.; Pardoll, D. M.; Elisseeff, J. H.
Show abstract
Fibrosis plays a key role in both chronic disease progression and failure of synthetic biomaterial implants. However, the contribution of adaptive immunity to fibrotic development remains incompletely understood, particularly for regulatory T cells (Tregs). Here, we used single-cell multiomic profiling, integrating transcriptomics with T cell receptor (TCR) sequencing, to map Treg heterogeneity and clonal dynamics in a synthetic material-induced model of fibrosis. We uncovered progressive Treg clonal expansion accompanied by TCR activation signatures and an increasingly immunosuppressive phenotype along a continuous transcriptional trajectory. These Tregs suppressed immune responses and influenced extracellular matrix and vascular gene expression. Cell-cell communication inference predicted Treg-driven activation of pro-fibrotic and vasculogenic transcriptional programs in fibroblasts and endothelial cells, including Sox-family transcription factors. Functional Treg depletion increased inflammation and significantly reduced neovascularization. Together, these findings identify Treg functions in the fibro-vascular niche through stromal cell modulation, highlighting immune-stromal interactions as an important axis in fibrosis.
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