Loss of effector Treg signature in APOB-reactive CD4+ T cells in patients with coronary artery disease.

Atherosclerosis underlies most coronary artery disease (CAD). It involves a significant autoimmune component against apolipoprotein B (APOB). In this study, we used short activation-induced marker (AIM) assays to characterize APOB-reactive CD4⁺ T cells in patients with angiographically verified CAD. APOB-reactive CD4⁺ T cells expressing CD25 and 4-1BB markers were the most abundant. Their frequency correlated positively with CAD severity. Transcriptomic analysis revealed that these cells were clonally expanded and significantly enriched in genes expressed in tissue-homing effector regulatory T (eT_reg) cells. They shared signatures with CD4⁺ T cells in mouse and human plaques, including expression of the plaque-homing chemokine receptor CXCR6. With increasing disease severity, the T_reg signature was progressively and significantly lost. Conversely, APOB-specific T_reg cells from patients with severe CAD gained glycolytic and interferon response signatures. We conclude that mild CAD is associated with a regulatory program in APOB-reactive CD4⁺ T cells, which is replaced by a pro-inflammatory program in patients with severe CAD.