MHC class II tetramers identify apolipoprotein B-specific CD4 T cells in mice and humans

Abstract

Abstract Immunization with atherosclerotic plaque antigens including MHC-II-restricted peptides from apolipoprotein B (ApoB, core protein of low density lipoprotein, LDL) is known to be atheroprotective in animal models. Herein we report a human ApoB peptide whose sequence is identical to mouse ApoB and which binds to both mouse (I-Ab) and human MHC class II. Immunization with this peptide reduced atherosclerotic plaque in the aortas of Apoe−/− mice fed with a Western diet and induced IL-10 producing CD25+FoxP3+ regulatory T cells (Tregs). After peptide restimulation in vivo, responding CD4+ T cells (by Nur77-GFP) were highly enriched in CD25+FoxP3+ Tregs. Using a novel I-Ab tetramer reagent, we further showed that peptide-specific CD4+ T cells expand upon vaccination, ~50% express FoxP3, and were 10-fold enriched for IL-10 producers. In human peripheral blood mononuclear cells (PBMCs) from individuals assessed for subclinical cardiovascular disease, ApoB-specific CD4+ T cells were detected using novel HLA-DR1/ApoB peptide tetramers. Peptide-specific CD4+ T cells from donors with carotid artery plaques showed more RORγt expression and less FoxP3 expression compared to those without. This is the first demonstration of ApoB-specific CD4+ T cells by tetramer in humans and the first animal model evidence of atheroprotective vaccination with a human ApoB peptide.