https://doi.org/10.1007/s00392-025-02625-4
1Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg im Breisgau, Deutschland
Atherosclerosis and its clinical complications, such as myocardial infarction and stroke represent the leading causes of mortality worldwide. Atherosclerosis is caused by a chronic inflammation of the vessel wall that is accompanied by a strong autoimmune response that involves auto-reactive T cells in lymph nodes and atherosclerotic plaques as well as autoantibodies that recognize low-density lipoprotein (LDL) and peptides from its main protein component Apolipoprotein B-100. Here, we investigate the potential of ApoB-specific vaccination to induce therapeutic immunomodulation of atherosclerosis in preclinical in vitro, in vivo and ex vivo models.
Results
Throughout the inflammatory response that accompanies experimental murine atherosclerosis, auto-reactive CD4+ T-helper cells accumulated in the atherosclerotic plaque. ApoB+ T-helper cells in lymph nodes contained a higher proportion of effector memory T cells (TEM, CD62L-CD44+) and central-memory T cells (TCM, CD62L+CD44+). The proportion of TEM-cells among ApoB+ T-helper cells was elevated in atherosclerosis-prone Apoe-/- mice compared with WT mice. This suggests that ApoB+ T-helper cells are activated under conditions of atherosclerosis. Likewise, we found that ApoB-reactive T-helper cells expand in the setting of atherosclerosis. Furthermore, ApoB+ FoxP3+ Tregs expressed higher levels of the atheroprotective cytokine IL-10 compared with ApoBneg Tregs suggesting a potential protective function of ApoB-reactive Tregs. Flourospot testing of T cells from atherosclerotic mice confirmed a IL-10 dominated cytokine signature of apoB-specific T cells. Vaccination with peptide ApoB induced a peptide- and site- specific T cell response in atherosclerotic mice and ameliorated de novo atherosclerosis in preclinical mouse models.
Conclusion
ApoB-specific vaccination has the potential to induce ApoB-specific regulatory CD4+ T cells that act anti-inflammatory likely by an IL-10 dependent mechanism.