CCL19+ fibroblast–CCR7+ T-cell crosstalk coordinates immunofibrotic signalling networks in systemic sclerosis

BACKGROUND: Understanding the roles of diverse fibroblast subsets is of great importance in elucidating the pathogenesis of systemic sclerosis (SSc). How the immunoregulatory function of fibroblasts contributes to the pathology of SSc remains poorly understood. OBJECTIVES: To explore how fibroblasts promote fibrosis through immunoregulatory signalling and crosstalk with immune cells in SSc. METHODS: Skin and blood samples from seven patients with SSc and four healthy control participants were analysed with single-cell RNA sequencing (scRNAseq). Key findings were confirmed by multiplex immunohistochemistry and flow cytometry. CCL19 expression in fibroblasts was measured in response to exogenous stressors in vitro. The functional role of the CCL19-CCR7 axis was further validated using a bleomycin-induced SSc mouse model. RESULTS: CCL19+ fibroblasts were upregulated in the dermis of patients with SSc and exhibited high expression of immunoregulatory genes. CCL19 expression correlated with the severity of dermal fibrosis in SSc, and these CCL19+ fibroblasts could be induced by vascular endothelial growth factor A (VEGFA). Spatial analysis revealed that CCL19+ fibroblasts were located in the T-cell-enriched niche in SSc skin. The most significant ligand-receptor interaction between CCL19+ fibroblasts and T cells in SSc skin was CCL19-CCR7. Furthermore, CCR7+ T cells, particularly CCR7+ CD8+ T cells, displayed profibrotic properties in SSc with enhanced cytotoxicity and actively interacting with extracellular matrix-producing fibroblasts. Blocking the CCL19-CCR7 axis alleviated dermal fibrosis in the bleomycin-induced SSc mouse model. Trajectory pseudo-time analysis of paired scRNAseq from peripheral blood and skin T cells indicated that skin-infiltrating CCR7+ T cells might originate from peripheral blood. CONCLUSIONS: CCL19+ fibroblasts, potentially induced by VEGFA, may remodel profibrotic immune niches by promoting the infiltration of CCR7+ T cells, driving the progression of fibrosis in SSc.