| Summary: | Atherosclerosis is a chronic inflammatory condition of the arterial wall that leads to the formation of vessel-occluding plaques within the subintimal space of middle-sized and larger arteries. While traditionally understood as a myeloid-driven lipid-storage disease, growing evidence suggests that the accumulation of low-density lipoprotein cholesterol (LDL-C) ignites an autoimmune response with CD4<sup>+</sup> T-helper (T<sub>H</sub>) cells that recognize self-peptides from Apolipoprotein B (ApoB), the core protein of LDL-C. These autoreactive CD4<sup>+</sup> T cells home to the atherosclerotic plaque, clonally expand, instruct other cells in the plaque, and induce clinical plaque instability. Recent developments in detecting antigen-specific cells at the single cell level have demonstrated that ApoB-reactive CD4<sup>+</sup> T cells exist in humans and mice. Their phenotypes and functions deviate from classical immunological concepts of distinct and terminally differentiated T<sub>H</sub> immunity. Instead, ApoB-specific CD4<sup>+</sup> T cells have a highly plastic phenotype, can acquire several, partially opposing and mixed transcriptional programs simultaneously, and transit from one T<sub>H</sub> subset into another over time. In this review, we highlight adaptive immune mechanisms in atherosclerosis with a focus on CD4<sup>+</sup> T cells, introduce novel technologies to detect ApoB-specific CD4<sup>+</sup> T cells at the single cell level, and discuss the potential impact of ApoB-driven autoimmunity in atherosclerosis.
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