T cell subsets and functions in atherosclerosis

Abstract

Atherosclerosis is a chronic inflammatory disease of the arterial wall and the primary underlying cause of cardiovascular disease. Data from in vivo imaging, cell-lineage tracing and knockout studies in mice, as well as clinical interventional studies and advanced mRNA sequencing techniques, have drawn attention to the role of T cells as critical drivers and modifiers of the pathogenesis of atherosclerosis. CD4⁺ T cells are commonly found in atherosclerotic plaques. A large body of evidence indicates that T helper 1 (T_H1) cells have pro-atherogenic roles and regulatory T (T_reg) cells have anti-atherogenic roles. However, T_reg cells can become pro-atherogenic. The roles in atherosclerosis of other T_H cell subsets such as T_H2, T_H9, T_H17, T_H22, follicular helper T cells and CD28^null T cells, as well as other T cell subsets including CD8⁺ T cells and γδ T cells, are less well understood. Moreover, some T cells seem to have both pro-atherogenic and anti-atherogenic functions. In this Review, we summarize the knowledge on T cell subsets, their functions in atherosclerosis and the process of T cell homing to atherosclerotic plaques. Much of our understanding of the roles of T cells in atherosclerosis is based on findings from experimental models. Translating these findings into human disease is challenging but much needed. T cells and their specific cytokines are attractive targets for developing new preventive and therapeutic approaches including potential T cell-related therapies for atherosclerosis.

Fig. 1 |. Role of T helper cells and regulatory T cells in the pathogenesis of atherosclerosis.

a | Naive CD4⁺ T helper (T_H) cells are primed in secondary lymphoid organs. T_H cells acquire the complete phenotype of effector T (T_eff) cells or regulatory T (T_reg) cells after encountering antigenic peptides from apolipoprotein B (ApoB) presented by antigen-presenting cells (APCs). APCs take up and process oxidized LDL (oxLDL), migrate to the draining lymph node and present peptides from ApoB on major histocompatibility complex (MHC) class II molecules. Naive T cells recognize this complex through their specific T cell receptors (TCRs). Co-stimulatory molecules induce T cells to express transcription factors that favour the differentiation into distinct T_H phenotypes. Homing receptors promote T cell migration to atherosclerotic lesions, where they secrete effector cytokines. b-c | CD4⁺ T cells can act in a pro-atherogenic or atheroprotective manner. Atherosclerotic lesions contain T_H1, T_H2, T_H9, T_H17, T_H22, T_reg, type 1 regulatory T (Tr1) cells and follicular helper T (T_FH) cells. T_reg cells can convert to ‘exT_reg cells (loss of CD25 and FoxP3)’ (dashed arrows), acquiring properties of other T_H phenotypes such as T_H1, T_H17 and T_FH. Instability of forkhead box protein P3 (FOXP3) expression triggers the formation of antigen-specific, but dysfunctional, partially non-protective exT_reg cells. AHR, aryl hydrocarbon receptor; BCL6, B-cell lymphoma 6; CCR5, C-C chemokine receptor type 5; CXCR3, C-X-C chemokine receptor type 3; EC, endothelial cell; G-CSF, granulocyte colony-stimulating factor; GATA3, GATA-binding factor 3; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFNγ, interferon-γ; LAG3, lymphocyte activation gene 3 protein; OxPL, oxidized phospholipid; PL, phospholipid; RORγt, nuclear receptor RORγt; T-bet, T-box transcription factor TBX21; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor; VSMC, vascular smooth muscle cell, VCAM1; vascular cell adhesion molecule 1.

Fig. 2 |. Role of CD8⁺ T cells, iNKT cells and γδT cells in atherosclerosis.

a | Overview of atheroprotective and pro-atherogenic functions of CD8⁺ T cells. The cytotoxic activity of CD8⁺ T cells towards atherosclerotic lesion-stabilizing cells, such as vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), and the secretion of interferon-γ (IFNγ), tumour necrosis factor (TNF) and other pro-inflammatory cytokines exacerbate the inflammatory responses and drive the progression and destabilization of atherosclerotic lesions. Regulatory CD8⁺ T cell subsets can have atheroprotective effects, with high cytotoxic activity towards antigen-presenting cells (APCs) and inhibition of CD4⁺ T cell polarization into pro-atherogenic phenotypes. b | Invariant natural killer T (iNKT) cells can be activated by the interaction of the T cell receptor (TCR) with CD1d molecules containing antigenic glycolipids present on APCs. iNKT cells can also be activated in a CD1d-independent manner by Toll-like receptor stimulation and by the activation of APCs, which in turn secrete cytokines that activate iNKT cells, such as IL-12 and IL-18. Activation of iNKT cells results in the rapid release of T_H1, T_H2 and T_H17 associated cytokines, which activate other immune cells in the atherosclerotic lesion. iNKT cells can also promote atherosclerosis by the induction of apoptosis of plaque cells through the release of cytotoxic proteins such as perforin and granzyme B. c | γδT cells are among the T cell subsets described in mouse atherosclerotic lesions. The intracellular cholesterol content in γδT cells regulates their activation, proliferation and effector functions. In addition, γδT cells are an abundant source of IL-17; therefore, these cells could modulate atherosclerosis via IL-17 production. However, the exact role of γδT cells in atherosclerosis is unclear.

Fig. 3 |. Tools for sampling and analysis of T cells in atherosclerosis.

a | Advanced percutaneous catheter devices can be used to sample the boundary layer of blood close to the vessel wall upstream and downstream of intact and disrupted human coronary atherosclerotic plaques or to sample plaque debris generated by plaque disruption through stent placement. A distal protection device can be positioned in the coronary artery downstream from the atherosclerotic plaque. b | Tetramer technology to identify apolipoprotein B (ApoB)-specific T cells. The tetramer reagent consist of four specific recombinant major histocompatibility complex (MHC) class II molecules tetramerized with streptavidin (SA) and loaded with ApoB-peptide for detecting ApoB-specific T cell receptors. c | Single-cell RNA sequencing (scRNA-seq), cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and mass cytometry (CyTOF) provide deep transcriptome data, cell surface phenotypes and T cell receptor sequencing data for ApoB-specific T cells in atherosclerosis.