Tfh cell communication with myeloid compartments plays a key role in the inflammatory response in localized scleroderma: insights from skin scRNA sequencing.

Abstract

Macrophages, T lymphocytes and NK cells are central to inflammatory responses in localized scleroderma (LS morphea), but their inflammatory signature and differentiation remain inadequately classified. This study examined the transcriptomes of these cell types to clarify their contribution to LS pathogenesis. Single-cell RNA sequencing was performed on LS skin. Ligand-receptor interaction and spatial transcriptomics confirmed the location of the altered immune phenotypes. Seventeen main cell types were identified, with focus on T cells, NK cells macrophages and dendritic cells (DCs). While LS and healthy samples show similar proportions of T and NK subpopulations, T follicular helper-like cells were more prevalent in LS. Myeloid populations showed more distinct stratification. TREM2+ and FCN1+ macrophages, and LAMP3+ DCs were expanded in LS, displaying an interferon signature consistent with an inflammatory phenotype. Ligand-receptor analysis demonstrated increased signaling interactions between T/NK cells and myeloid cells in LS, with pathways such as CXCL, CCL, TNF, and INF-II playing important roles. This scRNAseq study identifies expanded FCN1+ and TREM2+ macrophages and T follicular helper-like cells in untreated LS skin, highlighting immune dysregulation and offering insights into potential therapeutic targets.