T Cells in Atherosclerosis: Key Players in the Pathogenesis of Vascular Disease

Abstract

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-rich plaques within arterial walls. T cells play a pivotal role in the pathogenesis of atherosclerosis in which they help orchestrate immune responses and contribute to plaque development and instability. Here, we discuss the recognition of atherosclerosis-related antigens that may trigger T cell activation together with additional signaling from co-stimulatory molecules and lesional cytokines. Although few studies have indicated candidates for the antigen specificity of T cells in atherosclerosis, further research is needed. Furthermore, we describe the pro-atherogenic and atheroprotective roles of diverse subsets of T cells such as CD4⁺ helper, CD8⁺ cytotoxic, invariant natural killer, and γδ T cells. To classify and quantify T cell subsets in atherosclerosis, we summarize current methods to analyze cellular heterogeneity including single cell RNA sequencing and T cell receptor (TCR) sequencing. Further insights into T cell biology will help shed light on the immunopathology of atherosclerosis, inform potential therapeutic interventions, and pave the way for precision medicine approaches in combating cardiovascular disease.

Keywords: T cells; atherosclerosis; cardiovascular disease; inflammation.

Figure 1

Role of T cell subsets in atherosclerosis. Lesional T cells can be broken up into three groups including T cells with α and β chains within their T cell receptor (TCR) like CD4⁺ T cells (middle) and CD8⁺ T cells (right) as well as non-conventional T cells that follow different activation pathways (left). Non-conventional T cells include the pro-atherogenic invariant natural killer T (iNKT) cells that express various T helper (T_h) cytokines as well as interleukin (IL)-17 expressing γδ T cells. CD4⁺ T cells include T_h subsets such as pro-atherogenic T_h1 that express interferon-γ, controversial T_h2 that expresses IL-4 and IL-13, and T_h17 that expresses IL-17. Follicular T helper (T_FH) cells as well as CD28^null T cells are both CD4⁺, which are pro-atherogenic. Additionally, regulatory T (Treg) are atheroprotective CD4⁺ T cells; however, in late stage atherosclerosis, they convert to pro-atherogenic ex-Tregs. Finally, CD8⁺ T cells can infiltrate atherosclerotic plaques as well, but their role remains unclear. Created with biorender.com.