ApoB-Specific CD4⁺ T Cells in Mouse and Human Atherosclerosis

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⁺ T-helper (T_H) cells that recognize self-peptides from Apolipoprotein B (ApoB), the core protein of LDL-C. These autoreactive CD4⁺ 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⁺ T cells exist in humans and mice. Their phenotypes and functions deviate from classical immunological concepts of distinct and terminally differentiated T_H immunity. Instead, ApoB-specific CD4⁺ T cells have a highly plastic phenotype, can acquire several, partially opposing and mixed transcriptional programs simultaneously, and transit from one T_H subset into another over time. In this review, we highlight adaptive immune mechanisms in atherosclerosis with a focus on CD4⁺ T cells, introduce novel technologies to detect ApoB-specific CD4⁺ T cells at the single cell level, and discuss the potential impact of ApoB-driven autoimmunity in atherosclerosis.