Tissue-resident, circulating and plaque-homing CD4+ T cells in human atherosclerosis 2309197

Abstract Introduction Subsets of T cells have been shown to home to atherosclerotic plaque in atherosclerosis patients. In mice, CXCR6 and CCR5 play roles in mediating T cell recruitment to atherosclerotic lesions. We hypothesized that human T cell subsets possess the capacity to traffic between blood and atherosclerotic plaque. CD4+ regulatory T cells (Tregs) are known to give rise to exTregs, but their differentiation in atherosclerosis remains unclear. To address these gaps, we integrated CITE-seq datasets of PBMC and plaque from patients, focusing on αβ CD4+ T cells composition, migratory signatures, and differentiation between blood and plaque. Methods We analyzed CITE-seq datasets from a total of 12 patients aged over 69 years (6 PBMCs and 6 plaque). Data was integrated using LIGER. αβ CD4+ T cells were subset for re-clustering. TCR-seq data was used to assess clonal expansion across CD4+ T cell subsets. Trajectory analyses were used to infer differentiation relationships. pySCENIC was preformed to infer transcription factor activity. Results Integrated analysis showed enrichment of mast cells and NKT cells in plaque, while NK cells, classical monocytes, and CD4+ T cells predominated in blood. CD4+ T cell re-clustering identified naive, effector, memory, cytotoxic, and regulatory subsets. Naive and effector CD4+ T cells were blood-enriched, whereas cytotoxic effector memory CD4+ T cells and FoxP3hi Tregs were enriched in plaque. Cytotoxic CD4+ T cells expressed CCL5, GZMA, and GZMK, consistent with cytotoxic exTregs. FoxP3hi Tregs showed an activated phenotype distinct from FoxP3low Tregs. CXCR6 and CCR5 marked plaque-homing CD4+ T cells, with CCR7 supporting inter-compartment trafficking; CCR6 emerged as an additional pathway. Trajectory and TCR analyses supported differentiation from naive CD4+ T cells through unstable Tregs toward cytotoxic states, driven by ETV7 and GFI1 regulons. Conclusion Our study showed CD4+ T cell subset composition and differentiation between blood and plaque. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)