Oxidized LDL Induces Pro‐Inflammatory Transcriptomic and Epigenomic Responses in Human CD4 ⁺ T Cells

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 oxidized LDL (ox‐LDL) remains poorly understood. Therefore, we sought to characterize the transcriptomic and epigenomic consequences of ox‐LDL on activated human 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. By integrating our multiomic data, we identify the NRF1 and SP1 transcription factors as likely mediators of 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.