CD80 as an Important Immune Mediator and Therapeutic Target in Atherosclerosis

Atherosclerosis is a chronic immune–inflammatory disease of the arterial wall in which antigen-presenting cells (dendritic cells, macrophages and B cells) present locally generated antigens, such as oxidized low-density lipoprotein, to plaque-infiltrating T cells. Full T-cell activation requires costimulation through the B7 family ligands CD80 (B7-1) and CD86 (B7-2), which engage CD28 to activate T cells and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to restrain them. Although long considered functionally redundant, CD80 and CD86 are now known to be structurally and mechanistically distinct, differing in receptor affinity, susceptibility to CTLA-4-mediated trans-endocytosis, capacity to cis-heterodimerize with programmed death-ligand 1, and dependence relationships with regulatory versus effector T cells. In atherosclerosis, CD80 is expressed by lesional dendritic cells, macrophages, foam cells, B cells and, under inflammatory conditions, vascular endothelial and smooth muscle cells, with expression levels correlating with plaque vulnerability in humans. Genetic deletion, CTLA-4-Ig-based pharmacological blockade and selective small-molecule antagonism in preclinical models generally converge on a proatherogenic role for CD80/CD86-dependent costimulation, although combined genetic deletion of CD80 and CD86 has also been reported to paradoxically enhance early lesion formation in some contexts, while augmented CTLA-4-mediated coinhibition is atheroprotective—a balance corroborated by the accelerated atherosclerosis and cardiovascular toxicity observed with checkpoint-inhibitor cancer immunotherapy. Molecular imaging agents targeting CD80/CD86, repurposed CTLA-4-Ig biologics such as abatacept, and antigen-specific tolerogenic dendritic cell strategies together constitute an emerging translational pipeline. To our knowledge, this is the first review to integrate CD80’s structural and receptor pharmacology with its cellular sources in the plaque, preclinical genetic and pharmacological evidence, human plaque and biomarker data, molecular imaging approaches, and checkpoint inhibitor-associated cardiovascular toxicity within a single translational framework. This review synthesizes the structural biology, cellular sources, preclinical genetics, human plaque and biomarker data, and therapeutic and diagnostic implications of CD80 as an immune mediator and candidate therapeutic target in atherosclerosis.