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Induction of HLA-A2 restricted CD8 T cell responses against ApoB100 peptides does not affect atherosclerosis in a
Frank H Schaftenaar1, Jacob Amersfoort2, Hidde Douna2
1Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden, The Netherlands. f.h.schaftenaar@lacdr.leidenuniv.nl.
Insights
Targeting apolipoprotein B-100 (ApoB100) with CD8 T cells did not reduce atherosclerosis in mice. The atherosclerotic environment may impair T cell activation, hindering potential therapies.
Area of Science:
- Immunology
- Cardiovascular Science
- Atherosclerosis Research
Background:
- Cardiovascular diseases are a leading cause of death globally, primarily due to atherosclerosis.
- Atherosclerosis involves cholesterol-rich lipoprotein deposition and pathogenic immune responses, including macrophage accumulation and foam cell formation.
- Targeting macrophages within atherosclerotic plaques is a potential therapeutic strategy.
Purpose of the Study:
- To investigate if inducing a CD8 T cell response against apolipoprotein B-100 (ApoB100) can eliminate macrophages in atherosclerotic lesions.
- To assess the efficacy of ApoB100-specific CD8 T cells in reducing atherosclerosis progression.
Main Methods:
- In silico modeling identified 6 ApoB100-derived CD8 T cell epitopes.
- Peptides were synthesized, and HLA-A2 binding and T cell recall responses were assessed.
- ApoB100-specific CD8 T cell induction was evaluated in HLA-A2 and human ApoB100 transgenic LDLr-/- mice models.
- Plaque size, cellular composition, and T cell responses in spleen, lymph nodes, and aortic arch were analyzed.
Main Results:
- Five of six synthesized peptides induced CD8 T cell responses in vitro.
- Inducing ApoB100-specific CD8 T cells did not alter plaque size or composition in mouse models.
- T cell recall responses were detected in splenocytes and mesenteric lymph nodes but not in aortic arch cells.
- These findings suggest impaired CD8 T cell activation within the atherosclerotic environment.
Conclusions:
- CD8 T cell-mediated targeting of ApoB100 is not effective in reducing atherosclerosis in this mouse model.
- The local atherosclerotic environment may inhibit CD8 T cell function, posing a challenge for immunotherapy.
- Further research is needed to overcome immune suppression in atherosclerotic lesions for effective T cell-based therapies.
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.
