Background: Throughout the inflammatory response that accompanies atherosclerosis, autoreactive CD4 ⁺ T-helper cells accumulate in the atherosclerotic plaque. Apolipoprotein B ₁₀₀ (apoB), the core protein of low-density lipoprotein, is an autoantigen that drives the generation of pathogenic T-helper type 1 (T _H 1) cells with proinflammatory cytokine secretion. Clinical data suggest the existence of apoB-specific CD4 ⁺ T cells with an atheroprotective, regulatory T cell (T _reg ) phenotype in healthy individuals. Yet, the function of apoB-reactive T _regs and their relationship with pathogenic T _H 1 cells remain unknown. Methods: To interrogate the function of autoreactive CD4 ⁺ T cells in atherosclerosis, we used a novel tetramer of major histocompatibility complex II to track T cells reactive to the mouse self-peptide apo B _978-993 (apoB ⁺ ) at the single-cell level. Results: We found that apoB ⁺ T cells build an oligoclonal population in lymph nodes of healthy mice that exhibit a T _reg -like transcriptome, although only 21% of all apoB ⁺ T cells expressed the T _reg transcription factor FoxP3 (Forkhead Box P3) protein as detected by flow cytometry. In single-cell RNA sequencing, apoB ⁺ T cells formed several clusters with mixed T _H signatures that suggested overlapping multilineage phenotypes with pro- and anti-inflammatory transcripts of T _H 1, T helper cell type 2 (T _H 2), and T helper cell type 17 (T _H 17), and of follicular-helper T cells. ApoB ⁺ T cells were increased in mice and humans with atherosclerosis and progressively converted into pathogenic T _H 1/T _H 17-like cells with proinflammatory properties and only a residual T _reg transcriptome. Plaque T cells that expanded during progression of atherosclerosis consistently showed a mixed T _H 1/T _H 17 phenotype in single-cell RNA sequencing. In addition, we observed a loss of FoxP3 in a fraction of apoB ⁺ T _regs in lineage tracing of hyperlipidemic Apoe ^–/– mice. In adoptive transfer experiments, converting apoB ⁺ T _regs failed to protect from atherosclerosis. Conclusions: Our results demonstrate an unexpected mixed phenotype of apoB-reactive autoimmune T cells in atherosclerosis and suggest an initially protective autoimmune response against apoB with a progressive derangement in clinical disease. These findings identify apoB autoreactive T _regs as a novel cellular target in atherosclerosis.