Updated project metadata. Atherosclerosis has an auto-immune component driven by self-reactive T and B cells. Identifying their antigenic drivers may lead to new diagnosis and treatment approaches. Here, we aim to identify immunogenic T cell epitopes derived from atherosclerosis-relevant proteins such as ApoB100 by studying the repertoire of peptides presented by HLA in human plaques. We used immunopeptidomics to identify peptides presented by HLA-DR molecules in 51 plaques from patients that underwent endarterectomy surgery. We selected a set of 20 peptides derived from ApoB100 and studied the presence and cytokine profile of ApoB100-specific CD4+ T cells in peripheral blood mononuclear cells (PBMCs) from atherosclerosis patients. Results revealed significant CD4+ T cell activation in response to these ApoB100 peptides in 22.4% of the patients, and this T cell response correlated positively with plaque vulnerability. Furthermore, the cytokine profile of these cells was characterized by production both pro- and anti-inflammatory cytokines.