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Effects of fatty acids on T cell function: role in atherosclerosis

Nature Reviews Cardiology volume 18, pages 824–837 (2021)Cite this article

Subjects

Abstract

T cells are among the most common cell types present in atherosclerotic plaques and are increasingly being recognized as a central mediator in atherosclerosis development and progression. At the same time, triglycerides and fatty acids have re-emerged as crucial risk factors for atherosclerosis. Triglycerides and fatty acids are important components of the milieu to which the T cell is exposed from the circulation to the plaque, and increasing evidence shows that fatty acids influence T cell function. In this Review, we discuss the effects of fatty acids on four components of the T cell response — metabolism, activation, proliferation and polarization — and the influence of these changes on the pathogenesis of atherosclerosis. We also discuss how quiescent T cells can undergo a type of metabolic reprogramming induced by exposure to fatty acids in the circulation that influences the subsequent functions of T cells after activation, such as in atherosclerotic plaques.

Key points

  • Fatty acids in the circulation can affect T cell function.

  • Saturated fatty acids generally induce pro-inflammatory responses in T cells, whereas unsaturated fatty acids generally induce anti-inflammatory responses.

  • Changes in T cell metabolism underlie the fatty acid-induced alterations in T cell activation, proliferation and polarization.

  • Fatty acid-induced alterations in T cell function can in turn influence the development and progression of atherosclerosis.

  • Exposure to fatty acids in the circulation leads to metabolic reprogramming of the T cells that might predetermine the subsequent role of the T cell in disease processes.

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Fig. 1: Fatty acids alter T cell function by influencing their metabolism, activation, proliferation and polarization.
Fig. 2: Effects of circulating fatty acids on T cell functions in atherosclerosis.

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Acknowledgements

The authors’ work is supported by the Netherlands CardioVascular Research Initiative (The Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research and Development, and the Royal Netherlands Academy of Sciences) for the GENIUSII project Generating the Best Evidence-Based Pharmaceutical Targets for Atherosclerosis (CVON2011-19, CVON2017-20) and the Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL) administered by ZonMW, the Netherlands (grant 529051021).

Review criteria

We conducted a literature search divided into three main strategies. First, we searched for the four T cell responses, metabolism, activation, proliferation and polarization, together with different fatty acid names. Second, we searched for the four T cell responses in combination with the term “atherosclerosis”. Third, we searched fatty acid names in combination with the term “atherosclerosis”. The different T cell subsets (CD8+, CD4+, TH1, TH2, TH17 and Treg cells) were also used as search terms in combination with the groups listed above.

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Author notes

  1. These authors jointly supervised: Bastiaan T. Heijmans, J. Wouter Jukema.

Authors and Affiliations

  1. Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, Netherlands

    Nathalie A. Reilly & Bastiaan T. Heijmans

  2. Department of Cardiology, Leiden University Medical Centre, Leiden, Netherlands

    Nathalie A. Reilly & J. Wouter Jukema

  3. Department of Medical Biochemistry, Amsterdam University Medical Centre, Amsterdam, Netherlands

    Esther Lutgens

  4. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität, Munich, Germany

    Esther Lutgens

  5. German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany

    Esther Lutgens

  6. Leiden Academic Centre for Drug Research, Division of Biotherapeutics, Leiden University, Leiden, Netherlands

    Johan Kuiper

  7. Netherlands Heart Institute, Utrecht, Netherlands

    J. Wouter Jukema

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Contributions

N.A.R. researched data for the article and wrote the manuscript. B.T.H. and J.W.J. conceived and designed the content of the manuscript. All the authors provided substantial contributions to the discussion of content and reviewed and edited the manuscript before submission.

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Correspondence to J. Wouter Jukema.

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Glossary

T helper 1 cells

(TH1 cells). A subtype of CD4+ T cell characterized by the expression of the transcription factor T-bet and the production of pro-inflammatory cytokines, such as IFNγ, IL-2 and TNF. TH1 cells have been shown to be pro-atherogenic.

TH2 cells

A subtype of CD4+ T cell characterized by the expression of the transcription factor GATA3 and the production of anti-inflammatory cytokines, such as IL-4, IL-5 and IL-13. The role of TH2 cells in atherosclerosis is not completely clear, although anti-atherogenic properties have been described.

TH17 cells

A subtype of CD4+ T cell characterized by the expression of the transcription factor RORγt and the production of pro-inflammatory cytokines, such as IL-17A. The role of TH17 cells in atherosclerosis is undefined because they have been found to have both pro-atherogenic and anti-atherogenic properties.

Regulatory T cells

(Treg cells). A subtype of CD4+ T cell characterized by the expression of the transcription factor FOXP3 and the secretion of anti-inflammatory cytokines, such as IL-10 and TGFβ. Treg cells have been shown to have anti-atherogenic functions.

T cell tolerance

The process of eliminating T cells that are reactive to self-antigens. Tolerance can be induced by exposure to high doses of an antigen, which results in deletion or anergy of the T cells that are specific for that antigen.

Triglycerides

Esters formed by a glycerol and three fatty acid groups. High circulating levels of triglycerides have been associated with an increased risk of cardiovascular disease.

Polyunsaturated fatty acid

(PUFA). A fatty acid with a carbon chain that contains two or more double bonds. These fatty acids have a primarily anti-atherogenic effect.

Saturated fatty acids

(SFAs). Fatty acids with a carbon chain that contains no double bonds. These fatty acids have a primarily pro-atherogenic effect.

Monounsaturated fatty acids

(MUFAs). Fatty acids with a carbon chain that contains a single double bond. These fatty acids have both pro-atherogenic and anti-atherogenic effects.

Oxidative phosphorylation

The main form of energy production in quiescent T cells. High amounts of ATP are generated through the uptake of glucose and exogenous fatty acids to ensure cell survival.

Aerobic glycolysis

The main form of energy production in activated T helper cells, in which glucose is actively consumed to produce ATP and the necessary metabolites for cell growth and proliferation.

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Reilly, N.A., Lutgens, E., Kuiper, J. et al. Effects of fatty acids on T cell function: role in atherosclerosis. Nat Rev Cardiol 18, 824–837 (2021). https://doi.org/10.1038/s41569-021-00582-9

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