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Integrated bulk and single-cell transcriptomics identifies shared and specific immune signatures in Takayasu Arteritis

Kexin Xu,Taotao Li,Na Gao,Yaxin Zhang,Yi Yang,Honglei Zhao,Longfei Wang,Junmin Zhu,Jian Liu,L. Pan

Published 2025 in Arthritis Research & Therapy

ABSTRACT

Takayasu arteritis (TAK) is a rare, chronic large-vessel vasculitis. Although CD4⁺ and CD8⁺ T cells are acknowledged drivers of vascular injury in TAK, the gene networks that confer their pathogenicity remain incompletely mapped. This study aimed to integrate bulk RNA-sequencing of peripheral-blood T-cell subsets with single-cell RNA-sequencing of aortic tissue to find mechanistic biomarkers and therapeutic targets for TAK. We performed bulk RNA-sequencing on peripheral-blood CD4⁺ and CD8⁺ T cells from eight treatment-naïve TAK patients and three age matched healthy controls. In parallel, single-cell RNA-sequencing was applied to aortic tissue from three additional TAK patients and three atherosclerotic controls. DEGs were defined at false-discovery rate < 0.05. Functional enrichment used Gene Ontology, KEGG and Reactome. STRING constructed protein–protein interaction networks, and Cell Chat inferred intercellular ligand–receptor communication. Bulk profiling identified 851 DEGs in CD4⁺ and 1 645 DEGs in CD8⁺ T cells. CD4⁺ DEGs were enriched for inflammation, angiogenesis and platelet-activation pathways; CD8⁺ DEGs concentrated on cytokine synthesis, notably interleukin-1 signaling. Both subsets shared enrichment in complement cascade, focal adhesion and extracellular-matrix organization, indicating convergent pro-inflammatory programs. Single-cell analyses delineated dense CD4⁺– CD8⁺ crosstalk within TAK aorta and, relative to atherosclerotic controls, heat-shock protein binding and ubiquitin-ligase activity—hallmarks of heightened protein-homeostasis stress. Four transcriptional regulators—EGR1, KLF4, RHOB and ATF3—were consistently up-regulated in both blood and tissue; EGR1 showed the strongest fold-change and occupied a central hub in protein-interaction and ligand–receptor networks. In peripheral cells EGR1 co-clustered with cytokine-biosynthetic modules, while in tissue its profile mirrored the composite CD4⁺ and CD8⁺ signature, underscoring a unifying role in systemic and local inflammation. Integrated bulk and single-cell transcriptomics reveal both shared and subset-specific signaling landscapes for CD4⁺ and CD8⁺ T cells in TAK. The consistent prominence of EGR1 across compartments nominates this factor as a pivotal molecular switch and attractive therapeutic target. These data furnish a mechanistic framework for precision immune modulation in large-vessel vasculitis.

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