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.