Single-Cell RNA Sequencing Reveals Impaired Regulatory T Cell Function and a Pro-inflammatory Th17 Profile in Systemic Sclerosis

Abstract

ObjectiveThis resource deeply characterizes the CD4+ T cell subpopulations populations in SSc patients, with a novel single-cell RNA sequencing (scRNA-seq) approach, offering unprecedented insights into the cellular and molecular underpinnings of the disease. MethodsWe performed scRNA-seq to analyze over 80,000 CD4+ T cells from 8 SSc patients and 8 healthy controls, integrating abundance, transcriptional, and TCR repertoire analysis, to define CD4+ T cell subtype-specific signatures associated with SSc. ResultsSSc CD4+ T cells displayed a global interferon-driven activation signature and significantly reduced TNF signaling. Key transcriptomic alterations included the downregulation of SOX4 and CD83, alongside an expansion of Th2 and proinflammatory, steroid-resistant Th17 cells. Furthermore, Tregs exhibited a destabilized state characterized by high FCRL3 and reduced FOXP3 expression. Finally, TCR repertoire analysis identified increased clonal expansion specifically within the central memory (Tcm) compartment. ConclusionTogether, this data revealed SSc-associated cell population states in CD4+ T cells with unique transcriptomic signatures and provided a publicly accessible interactive platform to facilitate exploration of this dataset by the research community.