Atherosclerotic cardiovascular disease (ASCVD) is a chronic inflammatory disease characterized by the accumulation of lipoproteins and immune cell-rich plaques. The pathological progression of atherosclerosis is accelerated by the adaptive immune system, leading to a breakdown of tolerance to self-components. This breakdown is reflected in defective immune checkpoint molecule expression, dysfunctional antigen presentation, and aberrations in T cell populations, particularly regulatory T (Treg) cells. The loss of tolerance may be linked to the conversion of Treg cells to "exTreg" cells, which express T cell receptors specific for self-epitopes. Alternatively, it may trigger the activation of naive T cells, leading to the clonal expansion of pro-inflammatory and cytotoxic T cell populations. Recent studies using single-cell RNA sequencing have revealed that ApoB-specific CD4+ T cells in atherosclerosis exhibit clonal expansion and acquire effector phenotypes. The mechanisms underlying the breakdown of tolerance in atherosclerosis remain unclear, but potential candidates include Treg cell instability and dysfunction, as well as the activation of self-reactive naive T cells. Understanding these mechanisms could lead to the development of immunotherapeutic strategies to restore immune tolerance and prevent the progression of ASCVD.Atherosclerotic cardiovascular disease (ASCVD) is a chronic inflammatory disease characterized by the accumulation of lipoproteins and immune cell-rich plaques. The pathological progression of atherosclerosis is accelerated by the adaptive immune system, leading to a breakdown of tolerance to self-components. This breakdown is reflected in defective immune checkpoint molecule expression, dysfunctional antigen presentation, and aberrations in T cell populations, particularly regulatory T (Treg) cells. The loss of tolerance may be linked to the conversion of Treg cells to "exTreg" cells, which express T cell receptors specific for self-epitopes. Alternatively, it may trigger the activation of naive T cells, leading to the clonal expansion of pro-inflammatory and cytotoxic T cell populations. Recent studies using single-cell RNA sequencing have revealed that ApoB-specific CD4+ T cells in atherosclerosis exhibit clonal expansion and acquire effector phenotypes. The mechanisms underlying the breakdown of tolerance in atherosclerosis remain unclear, but potential candidates include Treg cell instability and dysfunction, as well as the activation of self-reactive naive T cells. Understanding these mechanisms could lead to the development of immunotherapeutic strategies to restore immune tolerance and prevent the progression of ASCVD.