Atherosclerosis is a chronic inflammatory disease of the arterial walls, characterized by the accumulation of oxidized lipoproteins and immune cells. It is associated with the breakdown of immune tolerance to self-antigens, leading to autoimmune responses. This breakdown is reflected in defective immune checkpoint molecules, dysfunctional antigen presentation, and altered T cell populations, particularly regulatory T cells (Treg). Tregs may convert to 'exTreg' cells, which exhibit pro-inflammatory and cytotoxic properties. Additionally, naive T cells may become activated, leading to the expansion of pro-inflammatory effector T cells. The autoimmune aspect of atherosclerosis is linked to the presence of autoantibodies against self-epitopes, such as those found in apolipoprotein B (ApoB)-containing lipoproteins. In mouse models, self-reactive CD4+ T cells contribute to the pathogenesis by mediating cytotoxic activity against host cells. The failure of immune tolerance in atherosclerosis is associated with the conversion of Treg cells to exTreg cells, which lose their regulatory function and gain pro-inflammatory properties. This process is influenced by factors such as chronic antigen exposure, pro-inflammatory signaling, and metabolic reprogramming. The mechanisms underlying this tolerance breakdown include the instability and dysfunction of Treg cells, leading to the activation of self-reactive T cells and the production of inflammatory cytokines. These findings highlight the autoimmune component of atherosclerosis and suggest that restoring immune tolerance could be a promising therapeutic approach. Future research should focus on understanding the different subpopulations of exTreg cells and the pathways involved in their conversion, as well as exploring potential therapeutic strategies to restore tolerance and prevent atherosclerosis progression.Atherosclerosis is a chronic inflammatory disease of the arterial walls, characterized by the accumulation of oxidized lipoproteins and immune cells. It is associated with the breakdown of immune tolerance to self-antigens, leading to autoimmune responses. This breakdown is reflected in defective immune checkpoint molecules, dysfunctional antigen presentation, and altered T cell populations, particularly regulatory T cells (Treg). Tregs may convert to 'exTreg' cells, which exhibit pro-inflammatory and cytotoxic properties. Additionally, naive T cells may become activated, leading to the expansion of pro-inflammatory effector T cells. The autoimmune aspect of atherosclerosis is linked to the presence of autoantibodies against self-epitopes, such as those found in apolipoprotein B (ApoB)-containing lipoproteins. In mouse models, self-reactive CD4+ T cells contribute to the pathogenesis by mediating cytotoxic activity against host cells. The failure of immune tolerance in atherosclerosis is associated with the conversion of Treg cells to exTreg cells, which lose their regulatory function and gain pro-inflammatory properties. This process is influenced by factors such as chronic antigen exposure, pro-inflammatory signaling, and metabolic reprogramming. The mechanisms underlying this tolerance breakdown include the instability and dysfunction of Treg cells, leading to the activation of self-reactive T cells and the production of inflammatory cytokines. These findings highlight the autoimmune component of atherosclerosis and suggest that restoring immune tolerance could be a promising therapeutic approach. Future research should focus on understanding the different subpopulations of exTreg cells and the pathways involved in their conversion, as well as exploring potential therapeutic strategies to restore tolerance and prevent atherosclerosis progression.