In this action, we found that ApoB-reactive T cells protect against early atherosclerosis, initially exhibiting a regulatory T cell (Treg) phenotype. Under hypercholesterolemia, they shift to pathogenic Th1/Th17 cells, driving inflammation. Using an MHC II tetramer, we identified these cells as an oligoclonal population with mixed Th1/Th17/Treg phenotypes in healthy mice. Single-cell RNA sequencing revealed overlapping pro- and anti-inflammatory transcripts. In atherosclerosis, ApoB-reactive T cells increased, shifting toward pathogenic Th1/Th17-like cells. Adoptive transfer showed converted ApoB+ T cells failed to protect, and circulating ApoB-reactive CD4+ T cells were more frequent in humans with atherosclerosis. This suggests an initially protective autoimmune response that becomes pathogenic, identifying ApoB-reactive T cells as a therapeutic target. Loss of FoxP3 drives the switch from protective to pathogenic phenotypes. Vaccination with ApoB-peptides boosts atheroprotection. Single-cell RNA sequencing revealed human plaques are T cell-dominated (over 60% of leukocytes), unlike myeloid-driven mouse plaques, highlighting a limited translatability of mouse models. Antibodies against ApoB-peptides correlated with clinical disease, implicating adaptive immunity in human atherosclerosis. B cells are essential for atheroprotective vaccination. Immunization with ApoB-peptides induced IL-10 in CD4+ T cells, but B cells were required for protection. HELMET Apoe-/- mice, lacking polyclonal B cells, failed to generate anti-ApoB antibodies or protection. Adding the cognate antigen HEL restored atheroprotection without anti-ApoB antibodies, showing T cell activation and BCR engagement are both necessary. IL-10 production, linked to BCR signaling, was critical, underscoring the importance of T and B cell collaboration. Immune cell transcriptomes predict cardiovascular outcomes. Single-cell and bulk RNA sequencing identified activation, memory formation, and proliferation pathways in CAD patients. Proliferating T and NK cells were associated with an increased risk, demonstrating immune cell transcriptomics' potential to refine risk prediction. Immune checkpoint inhibitors (ICIs) accelerated atherosclerosis, as shown by increased arterial [18F]FDG uptake in patients. This highlights ICIs' role in low-grade arterial inflammation but also [18F]FDG's variability in capturing vascular inflammation. ApoB-specific CD4+ T cells, enriched in circulating memory T cells (TCM), displayed a transitional immunophenotype, expressing both anti-inflammatory (IL-10) and pro-inflammatory (IFN-γ, TNF-α) cytokines. Their abundance correlated with cardiovascular risk, suggesting a role in atherogenesis. Plaque-resident T cells resembled ApoB+ T cells and plaque Treg cells with a Th17 phenotype, linking Treg destabilization to ApoB+ T cell function. Endothelial CD40 and CD40L promote plaque instability by recruiting inflammatory cells. Mice with endothelial-specific CD40 or CD40L deficiency developed smaller, more stable plaques with reduced macrophage content and increased collagen. Targeting these molecules may offer therapeutic strategies for atherosclerosis.
The following list gives an overview of the most important key findings:
1. Phenotype and function of ApoB-reactive T Cells in Atherosclerosis: One paper published, 4 more in preparation (ApoB-specific T cells in humans and correlation with clinical data / Systematic characterization of T cell phenotypes in mouse atherosclerosis / Inhibition of aged Tregs in mice / transcriptomes of aged Tregs in humans)
2. Immune Cell Transcriptomics and Cardiovascular Risk: 1 paper submitted, 1 more in preparation.
3. Impact of B Cells on Atheroprotective Vaccination: 1 paper published, 1 paper in revision, 2 more papers expected.
4. Differences in Human and Mouse Atherosclerosis: 1 paper published. 1 paper in submission.
5. Endothelial CD40 and CD40L in Atherosclerosis: 1 paper published, 1 paper in submission.
