Atherosclerosis is the buildup of fatty plaques in blood vessel walls that narrow and weaken those vessels, leading to rupture and a heart attack or stroke. While it is the innate immune cells known as macrophages that are responsible for removing excess lipids from blood vessel walls, clearing up the damage that leads to atherosclerotic plaques, atherosclerosis is a broadly inflammatory condition. Any contribution to systemic inflammatory signaling makes it harder for macrophages to do their job, and the aged adaptive immune system is just as much a source of inflammation as the aged innate immune system.
Whereas initiation of atherosclerotic plaques often occurs upon damage to the endothelium and subsequent infiltration of lipids into the vessel wall, its progression is marked by the infiltration of immune components leading to chronic inflammation of the plaque. Over time, the formation of necrotic debris, plaque destabilization and eventual rupture drive potentially fatal acute cardiovascular events such as a myocardial infarction or stroke. In light of the gradual functional decline of the aging immune system, it comes as no surprise that the incidence of acute cardiovascular events also greatly increases with age, even though atherosclerotic vascular changes already start occurring during early adolescence.
The hallmark feature of atherosclerotic plaque initiation is considered to be the accumulation of low density lipoproteins (LDL) in the tunica intima. This can occur due to a “leaky” endothelial cell layer of the vessel wall in response to damage, for example at sites of shear stress. Modification of LDL, primarily oxidation (oxLDL), promotes the recruitment and infiltration of monocytes into the vessel wall, and the subsequent accumulation of cholesterol-enriched foam cells that contribute to plaque growth and necrotic core formation. Adaptive immune responses, carried out by T cells and B cells, play a crucial role in atherosclerosis progression.
Distinct subsets of T cells, both effector memory T cells and regulatory T cells (Tregs), influence plaque development and stability. Notably, interferon gamma (IFNγ) secreting T helper (Th) 1 cells are the most common T cells found in atherosclerotic plaques. Th1 cells are considered pro-atherogenic, partially due to their role in stimulating macrophage polarization towards pro-inflammatory M1 effector cells. Advances in single cell technology further support the importance of adaptive immunity in atherosclerosis and revealed T-cells to be the most abundant leukocyte present in human carotid atherosclerotic plaques, outnumbering myeloid populations. Additionally, T cell receptor (TCR) sequencing has exposed plaque specific clonal expansion of CD4+ effector T cells with transcriptome profiles indicative of recent antigen-mediated T cell activation, thus suggesting an autoimmune component in atherosclerosis pathology.
Aging not only induces the expansion of pro-inflammatory and cytotoxic T cell subsets, but also stimulates an increase in T cells with regulatory phenotypes. An overall increase of Tregs was observed in the atherosclerotic aorta of aged LDLR knockout mice alongside a heightened expression of functional Treg markers and genes encoding for the IL-35 cytokine as compared to young mice. Similar upregulation of genes indicative of Treg activity was demonstrated in ex vivo human plaques. Moreover, Tregs show clonal expansion in the human carotid plaque. Previously, it has been reported that Treg functionality can decrease upon aging. Whether aging also impacts the immunosuppressive capacity of Tregs in the atherosclerotic environment, remains to be elucidated.