CD8+ T Cells in Atherosclerosis

Abstract

Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8⁺ T cells. The CD8⁺ T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8⁺ T cells ameliorates atherosclerosis. CD8⁺ T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8⁺ T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8⁺ T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8⁺ T cells and their cytotoxic activity. CD8⁺ T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25⁺CD8⁺ T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8⁺ T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8⁺ T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8⁺ T cells in atherosclerosis.

Keywords: CD8+ T cells; atherosclerosis; checkpoint inhibitors; cytotoxic T cells; immunotherapy; inflammation; single cell RNA sequencing.

Figure 1

CD8⁺ T cell functions in atherosclerosis. Immune cells including CD8⁺ T cells, infiltrate atherosclerotic lesions. CD8⁺ T cells are activated and expand locally in a potentially antigen-dependent manner. CD8⁺ T cells produce cytokines (TNF-α, IFN-γ) and cytotoxic mediators (granzyme, perforin), promoting plaque inflammation and cytotoxic cell death of macrophages, smooth muscle cells and endothelial cells. These effects promote expansion of the necrotic core, and a more instable plaque phenotype. In advanced atherosclerosis, CD8⁺ T cells are of reduced T-cell receptor (TCR) heterogeneity. Persistent activation may drive T cell exhaustion and reduced cytokine and cytotoxic functions. Activation of the Fas-FasL pathway induces apoptosis of foam cells and decreased Th1 T cell accumulation. Killing of macrophages may lower plaque burden but also increase inflammation in advanced atherosclerosis. Local cytotoxic responses towards endothelial cells may promote plaque erosion at culprit sites of acute coronary syndromes.

Figure 2

Activation of naïve CD8⁺ T cell subsets is based on the interaction of the T-cell receptor (TCR) with antigen presented on major histocompatibility class I (MHCI) by antigen-presenting cells (APC). Costimulatory or inhibitory signals, such as the CD28/CTLA-4 family of T cell regulators, promote or limit T cell responses.