Tolerance dysfunction in atherosclerosis may extend to checkpoints as varied as a shift from bona fide quiescence to an activated/memory-like phenotype within the naїve mature T cell pool in the circulation; clonal expansion of CD8+ T cells, CD4+ T cells and Treg cells with plaques being the most prominent tissue affected followed by ATLOs and RLNs; major alterations of transcript profiles including genes regulating migration/egress/residency, T cell activation, maintenance of effector and memory functions and exhaustion; and Treg–Th17 cell conversion. The gene discussed is CD4; the disease is atherosclerosis.