Circ Res. 2026 Jul 23. doi: 10.1161/CIRCRESAHA.125.326804. Online ahead of print.
ABSTRACT
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.
PMID:42488951 | DOI:10.1161/CIRCRESAHA.125.326804