Examining the effect of oxLDL on CD4+ T cell chromatin accessibility

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.