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  • Review Article
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T cell subsets and functions in atherosclerosis

Nature Reviews Cardiology volume 17, pages 387–401 (2020)Cite this article

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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 (TH1) cells have pro-atherogenic roles and regulatory T (Treg) cells have anti-atherogenic roles. However, Treg cells can become pro-atherogenic. The roles in atherosclerosis of other TH cell subsets such as TH2, TH9, TH17, TH22, follicular helper T cells and CD28null 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.

Key points

  • Atherosclerosis is a chronic inflammatory disease, and accumulating evidence supports the critical role of T cells as drivers and modifiers of this condition.

  • T cells drive immune responses to peptide epitopes related to atherosclerosis, such as peptides derived from apolipoprotein B.

  • CD4+ T helper 1 (TH1) cells and natural killer T cells have pro-atherogenic properties, whereas regulatory T (Treg) cells have anti-atherogenic functions.

  • The role of other TH cell subsets, such as TH2, TH9, TH17, TH22 and follicular helper T (TFH) cells, and of CD8+ T cells and γδ T cells, in the development and progression of atherosclerosis remains controversial.

  • During atherosclerosis progression, Treg cells can convert into pro-inflammatory T cell subsets, such as TH1, TH17 or TFH cells.

  • T cell recruitment to the atherosclerotic plaque occurs via chemokines and chemokine receptors such as CC-chemokine receptor 5 (CCR5), CXC-chemokine receptor 3 (CXCR3) and CXCR6.

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Fig. 1: Role of T helper cells and regulatory T cells in the pathogenesis of atherosclerosis.
Fig. 2: Role of CD8+ T cells, iNKT cells and γδ T cells in atherosclerosis.
Fig. 3: Tools for sampling and analysis of T cells in atherosclerosis.

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Acknowledgements

The authors’ work is funded by The National Institutes of Health, HL136275, HL140976, HL145241, HL146134, HL148094 to K.L., an overseas research fellowship from the Japan Society for the Promotion of Science to R.S., and a postdoctoral fellowship from the German government (DFG) to H.W.

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Authors and Affiliations

  1. Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA, USA

    Ryosuke Saigusa, Holger Winkels & Klaus Ley

  2. Department of Bioengineering, University of California San Diego, La Jolla, CA, USA

    Klaus Ley

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  1. Ryosuke Saigusa
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  2. Holger Winkels
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  3. Klaus Ley
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R.S. wrote the article. All authors researched data for the article, made substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Klaus Ley.

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K.L. is a founder of Atherovax. The other authors declare no competing interests.

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Glossary

Major histocompatibility complex

(MHC). Family of molecules that present antigen peptides to T cells. MHC class I molecules present peptides to CD8+ T cells and MHC class II molecules to CD4+ T cells. In humans, MHC molecules are very diverse (thousands of known alleles), but some alleles are more common (~10–20%) in some populations.

T cell receptor

(TCR). The TCR is a heterodimer that consists of either αβ or γδ chains, and expression of each heterodimer is mutually exclusive on the same cell. TCR signalling proceeds through transmembrane and intracellular CD3 subunits associated with the TCR. TCRs are highly polymorphic through recombination of V and J (and in some cases D) segments and through template-free nucleotide addition.

Co-stimulatory molecules

Co-stimulatory molecules are cell surface receptors that are ligated when the T cell receptor in T cells engages the major histocompatibility complex (MHC)–peptide complex in antigen-presenting cells. The nature of the co-stimulatory molecules determines the outcome of antigen presentation.

TCR sequencing

Technique that uses specific primers to identify the V, D and J segments used in each α, β, γ and δ subunit. The assembly of short reads and specialized reconstruction software such as TRACER allow the reconstruction of the entire T cell receptor (TCR) sequence, often of paired α and β or γ and δ chains.

MHC tetramer

Reagent used to analyse antigen-specific T cells. Constructed from four recombinant truncated major histocompatibility complex (MHC) class I or MHC class II molecules with the antigenic peptide naturally (non-covalently) or covalently bound and tetramerized by streptavidin. The streptavidin can be labelled by fluorochromes for detection with flow cytometry (Fig. 3b).

CD4+ effector memory T cells

A type of antigen-experienced CD4+ T cell that has effector functions but also forms memory (recall response after restimulation).

T cell exhaustion

Progressive loss of T cell functions under chronic antigen stimulation, for example, as occurs in cancer or persistent viral infections. Exhaustion can result in the depletion of the responding cells.

Innate lymphoid cells

Cells of the innate immune system with similarity to T helper cells in the expression of key transcription factors and effector molecules but that lack antigen-specific receptors characteristic of the adaptive immune system.

Necrotic core

The necrotic core of atherosclerotic lesions is composed of cholesterol crystals, debris of dead cells such as smooth muscle cells, foam cells and macrophages, and calcium particles. Large necrotic cores are associated with vulnerable plaques.

Central memory T cells

A type of antigen-experienced CD4+ T cells that has no effector functions but forms memory and is able to recirculate to secondary lymphoid organs.

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Saigusa, R., Winkels, H. & Ley, K. T cell subsets and functions in atherosclerosis. Nat Rev Cardiol 17, 387–401 (2020). https://doi.org/10.1038/s41569-020-0352-5

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