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Examining the effect of oxLDL on CD4+ T cell H3K27ac epigenetic marks

ABSTRACT: Elevated circulating low-density lipoprotein cholesterol (LDL-C) is a key risk factor for coronary artery disease (CAD). The pathogenesis of CAD is multifactorial, driven by heritable and lifestyle-related risk factors. Although CD4+ T cells are one of the main cell types in atherosclerotic lesions, their interaction with atherogenic oxidised LDL (ox-LDL) remains poorly understood. Therefore, we sought to characterise the transcriptomic and epigenomic consequences of ox-LDL on CD4+ T cells. We find that ox-LDL causes a shift towards a pro-inflammatory, cytokine-producing CD4+ T cell transcriptomic state. Concurrently, ox-LDL induces genome-wide changes in chromatin accessibility, notably in promoter regions. Multiomic data integration identifies a likely role for NRF1 and SP1 transcription factors in mediating ox-LDL-induced changes in gene expression. In contrast, the influence of AP-1 related factors over CD4+ T cell gene expression decreases following ox-LDL stimulation. We leveraged our multiomic data to investigate the disease-relevance of ox-LDL exposure, by investigating genomic locations where CAD-associated single nucleotide polymorphisms were found within dynamic ox-LDL-regulated accessible chromatin regions. Together, we demonstrate a disease-relevant role for ox-LDL in atherogenic conditioning of CD4+ T cells. Understanding such cell-type specific interactions with CAD risk factors may facilitate the development of targeted therapies for CAD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297906 | GEO | 2025/12/20

REPOSITORIES: GEO

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Project description:Background: The co-stimulatory CD40-CD40L dyad is an important driver of atherosclerosis. CD40 exerts divergent, cell-specific roles, which differentially impact atherogenesis. Objectives: We here investigate the role of the most prominent CD40-expressing cell-type, the B-cell, in atherosclerosis. Methods: B-cell subset specific CD40-expression of patients with mild and severe coronary artery disease (CAD) was determined by mass-cytometry and correlated to CAD severity. Underlying mechanisms were elucidated using B-cell CD40-deficient CD19Cre-CD40flfl-ApoE-/-(CD40BKO) mice and control littermates (CD40BWT). Results: Patients with severe CAD had similar CD40 expression levels on most B-cell subsets but showed a profound decrease in CD40 on putative B1 cells. This was associated with increased atherosclerotic plaque burden and decreased plaque fibrosis. Likewise, CD40BKO mice exhibited an increased plaque area and more advanced staging of atherosclerosis. Absence of CD40 on B-cells caused a decrease in immunoglobulin (Ig) producing cells, including germinal center-, plasma-, but especially B1 cells, thereby reducing levels of (anti-ox/MDA-LDL) IgG and protective (anti-ox/MDA-LDL) IgM. Transcriptomics analysis revealed that the absence of CD40 on B1b cells caused altered gene expression pathways related to lipid uptake (Cd36, Ldlr), cellular stress and metabolism (Nr4a1, Hif1a), and cell death (Naip5/6, Ccnd2). Indeed, in vitro analysis showed that B1bCD40KO cells took up excessive amounts of ac/oxLDL, exhibited defective BCR signaling, and were prone to apoptosis, especially in hyperlipidemic conditions. Transfer of wild-type B1b cells in CD40BKO mice prevented the increase in atherosclerosis. Conclusions: Patients with severe CAD had similar CD40 expression levels on most B-cell subsets but showed a profound decrease in CD40 on putative B1 cells. This was associated with increased atherosclerotic plaque burden and decreased plaque fibrosis. Likewise, CD40BKO mice exhibited an increased plaque area and more advanced staging of atherosclerosis. Absence of CD40 on B-cells caused a decrease in immunoglobulin (Ig) producing cells, including germinal center-, plasma-, but especially B1 cells, thereby reducing levels of (anti-ox/MDA-LDL) IgG and protective (anti-ox/MDA-LDL) IgM. Transcriptomics analysis revealed that the absence of CD40 on B1b cells caused altered gene expression pathways related to lipid uptake (Cd36, Ldlr), cellular stress and metabolism (Nr4a1, Hif1a), and cell death (Naip5/6, Ccnd2). Indeed, in vitro analysis showed that B1bCD40KO cells took up excessive amounts of ac/oxLDL, exhibited defective BCR signaling, and were prone to apoptosis, especially in hyperlipidemic conditions. Transfer of wild-type B1b cells in CD40BKO mice prevented the increase in atherosclerosis.

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Examining the effect of oxLDL on CD4+ T cell H3K27ac epigenetic marks

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