Single-cell transcriptome analysis identifies skin-specific T-cell responses in systemic sclerosis

Abstract

ObjectivesAlthough T cells have been implicated in the pathogenesis of systemic sclerosis (SSc), a comprehensive study of T-cell-mediated immune responses in the affected skin of patients with progressive SSc is lacking. Droplet-based single-cell transcriptome analysis of SSc skin biopsies opens avenues for dissecting patient-specific T-cell heterogeneity, providing a basis for identifying novel gene expression related to functional pathways associated with severity of SSc skin disease.MethodsSingle-cell RNA sequencing was performed by droplet-based sequencing (10x Genomics), focusing on 3729 CD3+ lymphocytes (867 cells from normal and 2862 cells from SSc skin samples) from skin biopsies of 27 patients with active SSc and 10 healthy donors. Confocal immunofluorescence microscopy of progressive SSc skin samples validated transcriptional results and visualised spatial localisations of T-cell subsets.ResultsWe identified several subsets of recirculating and tissue-resident T cells in healthy and SSc skin that were associated with distinct signalling pathways. While most clusters shared a common gene expression signature between patients and controls, we identified a unique cluster of recirculating CXCL13+ T cells in SSc skin which expressed a T helper follicular-like gene expression signature and that appears to be poised to promote B-cell responses within the inflamed skin of patients.ConclusionsCurrent available therapies to reverse or even slow progression of SSc lead to broad killing of immune cells and consequent toxicities, including death. Identifying the precise immune mechanism(s) driving SSc pathogenesis could lead to innovative therapies that selectively target the aberrant immune response, resulting in better efficacy and less toxicity.

Autoantibodies Targeting AT1- and ETA-Receptors Link Endothelial Proliferation and Coagulation via Ets-1 Transcription Factor

“…In a mouse model of salt-induced hypertension, Zhang et al showed that hypertensive vessels present increased smooth muscle cell populations, partly due to endothelial-to-mesenchymal cell transition [ 44 ]. In a context of systemic sclerosis, single-cell sequencing was used to study immune cell heterogeneity between patients and healthy controls using skin samples [ 45 ], or whole endothelial cell genetic patterns in individuals with or without the disease [ 46 ]. Such investigations would be of particular interest in blood vessels from SRC patients to identify the consequences of SRC-IgG on specific cell types.…”

Contributions of Immune Cells and Stromal Cells to the Pathogenesis of Systemic Sclerosis: Recent Insights

“…The receptors of γδ T cell are γ chain and δ chain which permit recognition of antigens without MHC restriction. In addition, a new subset of T cells in SSc skin likely promoting B-cell responses has been fully revealed by scRNA-seq which provides a fuller framework for understanding the contribution of T lymphocytes to autoimmunity (Gaydosik et al, 2021).…”

“…In this study, CXCL13 + T cells were adjacent to CD20 + B cells and expressed Tfh-related genes with lower levels like ICOS and PD1 but not BCL6 and CXCR5. Therefore, it may be a special Tfh subset, and treatment for CXCL13 + T cells may prevent disease progression (Gaydosik et al, 2021) (Figure 2).…”

Single Cell RNA Sequencing in Autoimmune Inflammatory Rheumatic Diseases: Current Applications, Challenges and a Step Toward Precision Medicine

“…Several T-lymphocyte subsets and associated cytokines have been implicated in the inflammatory and fibrotic processes of SSc, however their heterogeneity in SSc skin has only recently been revealed by Gaydosik et al ( 95 ). They detected several subsets of infiltrating, as well as tissue-resident T-lymphocytes in healthy and SSc skin that were enriched in different signaling pathways.…”

“…A significantly lower frequency of CD3 + CXCL13 + cells was detected in SSc patients treated with immunosuppressive drugs, compared with untreated patients. This indicates that a more targeted T cell-based therapy might be used in SSc patients, resulting in an improved efficacy and lower toxicity ( 95 ).…”