Autoreactive effector Treg cells with a compromised regulatory program in patients with coronary artery disease

Atherosclerosis, a pathological condition underlying cardiovascular diseases, involves chronic inflammation with a strong autoimmune component. Detailed molecular definition of autoreactive CD4+T cells in atherosclerotic patients is critical for understanding their role in disease pathogenesis. Apolipoprotein B (APOB) is a clinically relevant atherosclerosis-related autoantigen. Here, we used an activation-induced marker assay to conduct deep transcriptomic analyses of circulating APOB-reactive CD4+T cells from 40 patients with coronary artery disease. We identified autoreactive T cells expressing tissue-homing chemokine receptors and effector Treg signatures, suggesting recirculation of APOB-specific CD4+T cells between blood and atherosclerotic plaques. Treg gene signature and oligoclonality peaked in patients with mild disease, but declined in those with severe atherosclerosis. By contrast, clonal expansion and expression of effector molecules in inflammatory APOB-specific CD4+T cells increased with progressing disease severity. Thus, the autoimmune response in atherosclerosis starts with an atheroprotective regulatory program but switches to an inflammatory phenotype, likely accelerating disease progression.