Regulatory CD4+ T Cells Recognize MHC-II-Restricted Peptide Epitopes of Apolipoprotein B
Background—CD4+ T cells play an important role in atherosclerosis, but their antigen specificity is poorly understood. Immunization with apolipoprotein B (ApoB, core protein of low density lipoprotein) is known to be atheroprotective in animal models. Here, we report on a human APOB peptide, p18, that is sequence-identical in mouse ApoB and binds to both mouse and human MHC-II.
Methods—We constructed p18-tetramers to detect human and mouse APOB-specific T cells and assayed their phenotype by flow cytometry including CD4 lineage transcription factors, intracellular cytokines, and TCR activation. Apoe-/- mice were vaccinated with p18 peptide or adjuvants alone and atherosclerotic burden in the aorta was determined.
Results—In human peripheral blood mononuclear cells from donors without cardiovascular disease (CVD), p18 specific CD4+ T cells detected by a new HLA-DR-p18 tetramers were mostly Foxp3+ regulatory T cells (Tregs). Donors with subclinical CVD as detected by carotid artery ultrasound had Tregs co-expressing RORγt or T-bet which were both almost absent in donors without CVD. In Apoe-/- mice, immunization with p18 induced Tregs and reduced atherosclerotic lesions. After peptide restimulation, responding CD4+ T cells identified by Nur77-GFP were highly enriched in Tregs. A new mouse I-Ab-p18 tetramer identified the expansion of p18-specific CD4+ T cells upon vaccination, which were enriched for IL-10-producing Tregs.
Conclusions—These findings show that APOB p18 specific CD4+ T cells are mainly Tregs in healthy donors, but co-express other CD4 lineage transcription factors in donors with subclinical CVD. This study identifies ApoB peptide 18 as the first Treg epitope in human and mouse atherosclerosis.
- Received August 31, 2017.
- Revision received February 20, 2018.
- Accepted March 13, 2018.