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Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential

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Abstract

Atherosclerosis is a chronic inflammatory disease that is mediated by innate and adaptive immune responses. The disease is characterized by sub-endothelial accumulation and modification of lipids in the artery wall triggering an inflammatory reaction which promotes lesion progression and eventual plaque rupture, thrombus formation, and the respective clinical sequelae such as myocardial infarction or stroke. During the past decade, T-cell-mediated immune responses, especially control of pro-inflammatory signals by regulatory T cells (Tregs), have increasingly attracted the interest of experimental and clinical researchers. By suppression of T cell proliferation and secretion of anti-inflammatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor-β, Tregs exert their atheroprotective properties. Atherosclerosis-prone, hyperlipidemic mice harbor systemically less Tregs compared to wild-type mice, suggesting an imbalance of immune cells which affects local and systemic inflammatory and potentially metabolic processes leading to atherogenesis. Restoring or increasing Treg frequency and enhancing their suppressive capacity by various modulations may pose a promising approach for treating inflammatory conditions such as cardiovascular diseases. In this review, we briefly summarize the immunological basics of atherosclerosis and introduce the role and contribution of different subsets of T cells. We then discuss experimental data and current knowledge pertaining to Tregs in atherosclerosis and perspectives on manipulating the adaptive immune system to alleviate atherosclerosis and cardiovascular disease.

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Abbreviations

3-HAA:

3-Hydroxyanthranilic acid

AIRE:

Autoimmune regulator

AML1:

Acute myeloid leukemia 1 protein

APC:

Antigen-presenting cell

ApoB/E:

Apolipoprotein B/E

ATLO:

Artery tertiary lymphoid organ

CD:

Cluster of differentiation

CTLA-4:

Cytotoxic T-lymphocyte-associated protein-4

DC:

Dendritic cell

FcR:

Fc receptor

Foxp3:

Forkhead box P3

GARP:

Glycoprotein A repetitions predominant

HSP:

Heat shock protein

ICAM:

Intracellular adhesion molecule

IDO:

Indoleamine 2,3-dioxygenase

IFNγ:

Interferon gamma

Ig:

Immunoglobulin

IL:

Interleukin

LAP:

Latency-associated peptide

iNOS:

Inducible nitric oxide synthase

LDL(r):

Low-density lipoprotein (receptor)

MDA:

Malondialdehyde

MHC:

Major histocompatibility complex

mTEC:

Medullary thymic epithelial cells

NFAT:

Nuclear factor of activating T cells

NK cells:

Natural killer cells

Nrp-1:

Neuropilin 1

RA:

Rheumatoid arthritis

Rag:

Recombinase activating gene

RORγt:

Retinoic acid receptor-related orphan receptor

TCR:

T cell receptor

Tfr:

Follicular regulatory T cells

Tfh:

Follicular helper cells

TGFβ:

Transforming growth factor beta

Th cell:

T helper cell

TLR:

Toll-like receptor

TNF(R):

Tumor necrosis factor (receptor)

(i/n) Treg:

(Inducible/natural) regulatory T cells

SLO:

Secondary lymphoid organ

SMC:

Smooth muscle cell

VCAM:

Vascular cell adhesion molecule

VLDL:

Very low-density lipoprotein

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Acknowledgments

Research of the authors is supported by the Netherlands Cardiovascular Research Initiative (CVON-GENIUS), the Dutch Heart Foundation, Dutch Federation of University Medical Centers, the Netherlands Organization for Health Research and Development, the Royal Netherlands Academy of Sciences, the Humboldt Foundation (Sofia Kovalevskaja grant) (all to EL), the Netherlands Organization for Scientific Research (NWO) (VICI grant to EL, VICI grant to CW), the Netherlands Heart Foundation (Dr E. Dekker established investigator grant to EL), and the Deutsche Forschungsgemeinschaft (SFB 1054-B04 to EL and SFB 1123-A05 to EL and NG).

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Authors and Affiliations

  1. Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstr. 9, 80336, Munich, Germany

    Charlotte Spitz, Holger Winkels, Christina Bürger, Christian Weber, Esther Lutgens & Norbert Gerdes

  2. Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Holger Winkels & Esther Lutgens

  3. DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany

    Christian Weber

  4. Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden

    Göran K. Hansson

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  1. Charlotte Spitz
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  2. Holger Winkels
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Correspondence to Norbert Gerdes.

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Spitz, C., Winkels, H., Bürger, C. et al. Regulatory T cells in atherosclerosis: critical immune regulatory function and therapeutic potential. Cell. Mol. Life Sci. 73, 901–922 (2016). https://doi.org/10.1007/s00018-015-2080-2

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  • DOI: https://doi.org/10.1007/s00018-015-2080-2

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