Abstract
Cardiovascular diseases form the most common cause of death worldwide, with atherosclerosis as main etiology. Atherosclerosis is marked by cholesterol rich lipoprotein deposition in the artery wall, evoking a pathogenic immune response. Characteristic for the disease is the pathogenic accumulation of macrophages in the atherosclerotic lesion, which become foam cells after ingestion of large quantities of lipoproteins. We hypothesized that, by inducing a CD8 T cell response towards lipoprotein derived apolipoprotein-B100 (ApoB100), lesional macrophages, that are likely to cross-present lipoprotein constituents, can specifically be eliminated. Based on in silico models for protein processing and MHC-I binding, 6 putative CD8 T cell epitopes derived from ApoB100 were synthesized. HLA-A2 binding was confirmed for all peptides by T2 cell binding assays and recall responses after vaccination with the peptides proved that 5 of 6 peptides could induce CD8 T cell responses. Induction of ApoB100 specific CD8 T cells did not impact plaque size and cellular composition in HLA-A2 and human ApoB100 transgenic LDLr−/− mice. No recall response could be detected in cultures of cells isolated from the aortic arch, which were observed in cell cultures of splenocytes and mesenteric lymph nodes, suggesting that the atherosclerotic environment impairs CD8 T cell activation.
Highlights
Cardiovascular disease is the most common cause of death in the western world with atherosclerosis as the most common etiology[1]
To target CD8 T cells towards plaque macrophages which are likely to cross-present plaque derived antigens, we predicted putative HLA-A2 restricted CD8 T cell epitopes in human ApoB100 using in silico models for immunoproteasomal processing and TAP binding[26,27,28] and HLA-A2 binding models[28,29,30,31,32,33,34,35]
Recent studies suggest an overall pathogenic role for cytotoxic lymphocyte (CTL) through secretion of pro-inflammatory cytokines[4,5], which seems to correlate with observations of increased activated and cytokine producing CD8 T cells in peripheral blood of patients with coronary artery disease[43,44,45]
Summary
Cardiovascular disease is the most common cause of death in the western world with atherosclerosis as the most common etiology[1]. CD8 T cells in atherosclerotic lesions appear highly activated[3] suggesting a pathogenic role for CD8 T cells atherosclerosis. MHC-I/peptide complex recognition results in TNF-α and IFN-γ production by CTLs and leads to FAS ligand or perforin and granzyme B mediated cell death of the target cell[11]. The specificity of the TCR heavily impacts its pathogenicity, as depending on target antigen, vaccination induced CTLs can be atheroprotective[12,13,14,15] or atherogenic[16]. Presumable cross-presentation of LDL derived apolipoprotein-B100 (ApoB100) epitopes on MHC-I by lesional phagocytes, suggests that inducing ApoB100 specific CD8 T cells could lead to killing of lesional macrophages and reduce atherosclerosis. ApoB100 specific CTLs were induced by ApoB100 peptide vaccination, these CD8 T cells did not change cellular plaque composition, plaque collagen content, and plaque size, indicating that induction of ApoB100 specific CD8 T cells does not affect atherosclerosis
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