Breaking tolerance: the autoimmune aspect of atherosclerosis

Abstract

Atherosclerotic cardiovascular disease (ASCVD) is a chronic inflammatory disease of the arterial walls and is characterized by the accumulation of lipoproteins that are insufficiently cleared by phagocytes. Following the initiation of atherosclerosis, the pathological progression is accelerated by engagement of the adaptive immune system. Atherosclerosis triggers the breakdown of tolerance to self-components. This loss of tolerance is reflected in defective expression of immune checkpoint molecules, dysfunctional antigen presentation, and aberrations in T cell populations - most notably in regulatory T (T_reg) cells - and in the production of autoantibodies. The breakdown of tolerance to self-proteins that is observed in ASCVD may be linked to the conversion of T_reg cells to 'exT_reg' cells because many T_reg cells in ASCVD express T cell receptors that are specific for self-epitopes. Alternatively, or in addition, breakdown of tolerance may trigger the activation of naive T cells, resulting in the clonal expansion of T cell populations with pro-inflammatory and cytotoxic effector phenotypes. In this Perspective, we review the evidence that atherosclerosis is associated with a breakdown of tolerance to self-antigens, discuss possible immunological mechanisms and identify knowledge gaps to map out future research. Rational approaches aimed at re-establishing immune tolerance may become game changers in treating ASCVD and in preventing its downstream sequelae, which include heart attacks and strokes.

Fig. 1 |. Antigen presentation in atherosclerosis.

The adventitia of large arteries has afferent lymphatics that drain into local lymph nodes, but in the setting of atherosclerosis, how immune cells can migrate from the plaque to the adventitia is unknown. Antigen-presenting cells (APCs) may carry antigen from the artery to the draining lymph node, wherein they enter germinal centres (indicated by dashed lines) that are populated by B cells (blue) and some T cells (red). High endothelial venules (HEVs) are the gateways enabling entry of naive T cells from the blood into lymph nodes. In atherosclerosis, plaque forms a neointima (yellow) and low-density lipoprotein (LDL) accumulates and becomes oxidized. In the draining lymph node, some T cells undergo clonal expansion in response to arterial antigens including ApoB. Some T cells leave via efferent lymphatics and traverse the thoracic duct (dark blue-shaded area) to enter the blood circulation. Clonally expanded T cells home back to the plaque (arrows), some via CC-chemokine receptor 5 (CCR5)-mediated trafficking. Over time, arterial tertiary lymphatic organs form in the adventitia, wherein APCs encounter naive and antigen-experienced B cells and T cells. T cell clonal expansion is more extensive in arterial tertiary lymphoid organs (ATLOs) than in lymph nodes, suggesting that ATLOs may provide a ‘shortcut’ that accelerates autoimmunity in atherosclerosis. Some germinal centre B cells become plasma cells and secrete antibodies to atherosclerosis-associated antigens including oxidized LDL (not shown).

Fig. 2 |. Conversion of regulatory T cells in atherosclerosis.

FOXP3⁺CD25⁺CD127⁻ regulatory T (T_reg) cells (blue) can convert into at least four types of ‘exT_reg’ cells in atherosclerosis. In studies of the Apoe^−/− mouse model, T helper 1 (T_H1)-likeT_reg cells (yellow) have been described with a FOXP3^lowCD25⁻ T-bet⁺ CCR5⁺ phenotype^,. Another study has shown that T_reg cells become increasingly T_H17-like (orange) in response to a western diet. A similar T cell phenotype (FOXP3⁺RORγt⁺ T_H17-like) was shown by flow cytometry in patients with atherosclerosis. In Apoe^−/− mice, some exT_reg cells can acquire a T_FH-like phenotype (pink) and express CXCR5, PD1, BCL-6 and ICOS. In humans and mice with atherosclerosis, terminally differentiated cytotoxic exT_reg cells (red) express very low levels of FOXP3 and no CD25, but they acquire expression of CCL3, CCL4 and CCL5, TBX21, and a cytotoxic signature including NKG7 (ref. 29). The mechanisms that drive the conversion of T_reg cells to exT_reg cells are still unknown.

Fig. 3 |. Activation and expansion of naive T cells.

Dendritic cells (DCs) derived from plaques may enter draining lymph nodes through afferent lymphatics and present self-antigens on MHC class I (MHC-I) or MHC-II molecules to T cells in the context of co-stimulation. This can initiate the activation and clonal expansion of naive CD8⁺ or CD4⁺ T cells. These cells may acquire effector phenotypes, leave the lymph node through efferent lymphatics, and enter the circulation, homing back to atherosclerotic arteries^,. Whether such newly activated T cells acquire their effector programme at the site of initial antigen encounter (that is, in the draining lymph node) or in the peripheral (plaque) tissue is not known. HEV, high endothelial venule; TCR, T cell receptor.