Increased Autoreactive CD8 ⁺ T Cells to Apolipoprotein B Epitopes in Patients With Severe Coronary Artery Disease

BACKGROUND: Atherosclerosis is a chronic inflammatory disease with a strong autoimmune component, marked by the detection of autoreactive T cells and autoantibodies. Recent single-cell RNA sequencing studies have shown that atherosclerotic plaques contain clonally expanded CD8 + T cells. One of the known atherosclerosis autoantigens is APOB (apolipoprotein B). However, autoreactive CD8 + T cells to APOB in humans have not been described. METHODS: We studied CD8 + T-cell reactivity to human leukocyte antigen-A*02:01-restricted APOB epitopes, starting with in silico epitope prediction. We used peripheral blood mononuclear cells from human leukocyte antigen-A02:01+ healthy subjects to test the top 64-ranked peptides for their potential to elicit a CD8 + T-cell response. Antigen-specific responses were assessed using activation-induced marker assays, intracellular cytokine staining, and IFNγ (interferon gamma) ELISpot assays. RESULTS: Some APOB peptides triggered robust CD8 + T-cell activation with effector memory features, and expression of cytokines and cytotoxic molecules. Five immunodominant epitopes spanning 2 APOB regions accounted for most of the response and elicited significant T-cell activation in healthy donors that was increased in clinical samples from patients with severe coronary artery disease. CONCLUSIONS: The discovery of immunodominant major histocompatibility complex class I-restricted APOB epitopes suggests a new perspective for immune-based interventions to mitigate atherosclerosis.