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

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.

References

  1. 1.

    Schaftenaar, F., Frodermann, V., Kuiper, J. & Lutgens, E. Atherosclerosis: the interplay between lipids and immune cells. Curr. Opin. Lipidol. 27, 209–215 (2016).

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Barquera, S. et al. Global overview of the epidemiology of atherosclerotic cardiovascular disease. Arch. Med. Res. 46, 328–338 (2015).

    PubMed  Article  Google Scholar 

  3. 3.

    Brown, M. S. & Goldstein, J. L. How LDL receptors influence cholesterol and atherosclerosis. Sci. Am. 251, 58–69 (1984).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Brown, M. S. & Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science 232, 34–47 (1986).

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Tabas, I. & Lichtman, A. H. Monocyte-macrophages and T cells in atherosclerosis. Immunity 47, 621–634 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Hansson, G. K., Holm, J. & Jonasson, L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am. J. Pathol. 135, 169–175 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Jonasson, L., Holm, J., Skalli, O., Bondjers, G. & Hansson, G. K. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 6, 131–138 (1986).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Zhou, X., Nicoletti, A., Elhage, R. & Hansson, G. K. Transfer of CD4+ T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 102, 2919–2922 (2000).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Zhou, X., Robertson, A. K., Hjerpe, C. & Hansson, G. K. Adoptive transfer of CD4+ T cells reactive to modified low-density lipoprotein aggravates atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 26, 864–870 (2006).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Ketelhuth, D. F. & Hansson, G. K. Adaptive response of T and B cells in atherosclerosis. Circ. Res. 118, 668–678 (2016).

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Aukrust, P. et al. The complex role of T-cell-based immunity in atherosclerosis. Curr. Atheroscler. Rep. 10, 236–243 (2008).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Saigusa, R., Winkels, H. & Ley, K. T cell subsets and functions in atherosclerosis. Nat. Rev. Cardiol. 17, 387–401 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Cochain, C. & Zernecke, A. Protective and pathogenic roles of CD8+ T cells in atherosclerosis. Basic Res. Cardiol. 111, 71 (2016).

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    van Duijn, J., Kuiper, J. & Slutter, B. The many faces of CD8+ T cells in atherosclerosis. Curr. Opin. Lipidol. 29, 411–416 (2018).

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    van Duijn, J. et al. CD8+ T-cells contribute to lesion stabilization in advanced atherosclerosis by limiting macrophage content and CD4+ T-cell responses. Cardiovasc. Res. 115, 729–738 (2019).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Cochain, C. et al. CD8+ T cells regulate monopoiesis and circulating Ly6C-high monocyte levels in atherosclerosis in mice. Circ. Res. 117, 244–253 (2015).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Leistner, D. M. et al. Differential immunological signature at the culprit site distinguishes acute coronary syndrome with intact from acute coronary syndrome with ruptured fibrous cap: results from the prospective translational OPTICO-ACS study. Eur. Heart J. 41, 3549–3560 (2020).

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Winkels, H. et al. Atlas of the immune cell repertoire in mouse atherosclerosis defined by single-cell RNA-sequencing and mass cytometry. Circ. Res. 122, 1675–1688 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Fernandez, D. M. et al. Single-cell immune landscape of human atherosclerotic plaques. Nat. Med. 25, 1576–1588 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Depuydt, M. A. C. et al. Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics. Circ. Res. 127, 1437–1455 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Zernecke, A. et al. Meta-analysis of leukocyte diversity in atherosclerotic mouse aortas. Circ. Res. 127, 402–426 (2020).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Williams, J. W. et al. Single cell RNA sequencing in atherosclerosis research. Circ. Res. 126, 1112–1126 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Visscher, M. et al. Data processing pipeline for lipid profiling of carotid atherosclerotic plaque with mass spectrometry imaging. J. Am. Soc. Mass. Spectrom. 30, 1790–1800 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Stemme, S. et al. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc. Natl Acad. Sci. USA 92, 3893–3897 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Wolf, D. et al. Pathogenic autoimmunity in atherosclerosis evolves from initially protective apolipoprotein B100-reactive CD4(+) T-regulatory cells. Circulation 142, 1279–1293 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    van Puijvelde, G. H. et al. Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation 114, 1968–1976 (2006).

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Klingenberg, R. et al. Intranasal immunization with an apolipoprotein B-100 fusion protein induces antigen-specific regulatory T cells and reduces atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 30, 946–952 (2010).

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Tse, K. et al. Atheroprotective vaccination with MHC-II restricted peptides from ApoB-100. Front. Immunol. 4, 493 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Nilsson, J., Wigren, M. & Shah, P. K. Regulatory T cells and the control of modified lipoprotein autoimmunity-driven atherosclerosis. Trends Cardiovasc. Med. 19, 272–276 (2009).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    McNamara, D. J. Dietary cholesterol and atherosclerosis. Biochim. Biophys. Acta 1529, 310–320 (2000).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Talayero, B. G. & Sacks, F. M. The role of triglycerides in atherosclerosis. Curr. Cardiol. Rep. 13, 544–552 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Dron, J. S. & Hegele, R. A. Genetics of triglycerides and the risk of atherosclerosis. Curr. Atheroscler. Rep. 19, 31 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33.

    Nordestgaard, B. G. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease new insights from epidemiology, genetics, and biology. Circ. Res. 118, 547–563 (2016).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Keech, A. C. & Jenkins, A. J. Triglyceride-lowering trials. Curr. Opin. Lipidol. 28, 477–487 (2017).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Salakhutdinov, N. F. & Laev, S. S. Triglyceride-lowering agents. Bioorg. Med. Chem. 22, 3551–3564 (2014).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Budoff, M. Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. Am. J. Cardiol. 118, 138–145 (2016).

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Bhatt, D. L. et al. Effects of icosapent ethyl on total ischemic events from REDUCE-IT. J. Am. Coll. Cardiol. 73, 2791–2802 (2019).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Kersten, S. Triglyceride metabolism under attack. Cell Metab. 25, 1209–1210 (2017).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Kersten, S. Physiological regulation of lipoprotein lipase. Biochim. Biophys. Acta 1841, 919–933 (2014).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Ding, D. et al. Association between erythrocyte membrane n-3 and n-6 polyunsaturated fatty acids and carotid atherosclerosis: a prospective study. Atherosclerosis 298, 7–13 (2020).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Steffen, B. T., Duprez, D., Szklo, M., Guan, W. & Tsai, M. Y. Circulating oleic acid levels are related to greater risks of cardiovascular events and all-cause mortality: The Multi-Ethnic Study of Atherosclerosis. J. Clin. Lipidol. 12, 1404–1412 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Afonso, M. S. et al. Dietary interesterified fat enriched with palmitic acid induces atherosclerosis by impairing macrophage cholesterol efflux and eliciting inflammation. J. Nutr. Biochem. 32, 91–100 (2016).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Marangoni, F. et al. Dietary linoleic acid and human health: focus on cardiovascular and cardiometabolic effects. Atherosclerosis 292, 90–98 (2020).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Yang, Z. H. et al. Dietary palmitoleic acid attenuates atherosclerosis progression and hyperlipidemia in low-density lipoprotein receptor-deficient mice. Mol. Nutr. Food Res. 63, 1900120 (2019).

    Article  CAS  Google Scholar 

  46. 46.

    Gallagher, H. et al. Dihomo-γ-linolenic acid inhibits several key cellular processes associated with atherosclerosis. Biochim. Biophys. Acta Mol. Basis Dis. 1865, 2538–2550 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Noto, D. et al. Myristic acid is associated to low plasma HDL cholesterol levels in a Mediterranean population and increases HDL catabolism by enhancing HDL particles trapping to cell surface proteoglycans in a liver hepatoma cell model. Atherosclerosis 246, 50–56 (2016).

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Yamagishi, K., Nettleton, J. A., Folsom, A. R. & Investigators, A. S. Plasma fatty acid composition and incident heart failure in middle-aged adults: the Atherosclerosis Risk in Communities (ARIC) Study. Am. Heart J. 156, 965–974 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Valenzuela, C. A., Baker, E. J., Miles, E. A. & Calder, P. C. Eighteen-carbon trans fatty acids and inflammation in the context of atherosclerosis. Prog. Lipid Res. 76, 101009 (2019).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Delgado, G. E. et al. Individual omega-9 monounsaturated fatty acids and mortality – the Ludwigshafen Risk and Cardiovascular Health Study. J. Clin. Lipidol. 11, 126–135 (2017).

    PubMed  Article  Google Scholar 

  51. 51.

    Liu, L. et al. Protective role of n6/n3 PUFA supplementation with varying DHA/EPA ratios against atherosclerosis in mice. J. Nutr. Biochem. 32, 171–180 (2016).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Djousse, L., Matthan, N. R., Lichtenstein, A. H. & Gaziano, J. M. Red blood cell membrane concentration of cis-palmitoleic and cis-vaccenic acids and risk of coronary heart disease. Am. J. Cardiol. 110, 539–544 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Spigoni, V. et al. Stearic acid at physiologic concentrations induces in vitro lipotoxicity in circulating angiogenic cells. Atherosclerosis 265, 162–171 (2017).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Kelley, D. S. & Adkins, Y. Similarities and differences between the effects of EPA and DHA on markers of atherosclerosis in human subjects. Proc. Nutr. Soc. 71, 322–331 (2012).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Mensink, R. P., Zock, P. L., Kester, A. D. M. & Katan, M. B. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am. J. Clin. Nutr. 77, 1146–1155 (2003).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Polonskaya, Y. V. et al. Balance of fatty acids and their correlations with parameters of lipid metabolism and markers of inflammation in men with coronary atherosclerosis. Bull. Exp. Biol. Med. 164, 33–35 (2017).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Chung, H. K. et al. Plasma phospholipid arachidonic acid and lignoceric acid are associated with the risk of cardioembolic stroke. Nutr. Res. 35, 1001–1008 (2015).

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Ghoshal, S., Witta, J., Zhong, J., de Villiers, W. & Eckhardt, E. Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res. 50, 90–97 (2009).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Randolph, G. J. & Miller, N. E. Lymphatic transport of high-density lipoproteins and chylomicrons. J. Clin. Invest. 124, 929–935 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Ratnayake, W. M. & Galli, C. Fat and fatty acid terminology, methods of analysis and fat digestion and metabolism: a background review paper. Ann. Nutr. Metab. 55, 8–43 (2009).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Chowdhury, R. et al. Association of dietary, circulating, and supplement fatty acids with coronary risk. Ann. Intern. Med. 160, 398–406 (2014).

    PubMed  Article  Google Scholar 

  62. 62.

    Spady, K. D., Woollett, L. A. & Dietschy, J. M. Regulation of plasma LDL-cholesterol levels by dietary cholesterol and fatty acids. Annu. Rev. Nutr. 13, 355–381 (1993).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20, 55–70 (2020).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Sprent, J. & Surh, C. D. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat. Immunol. 12, 478–484 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Guermonprez, P., Valladeau, J., Zitvogel, L., Thery, C. & Amigorena, S. Antigen presentation and T cell stimulation by dendritic cells. Annu. Rev. Immunol. 20, 621–667 (2002).

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Geissmann, F. et al. Blood monocytes: distinct subsets, how they relate to dendritic cells, and their possible roles in the regulation of T-cell responses. Immunol. Cell Biol. 86, 398–408 (2008).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Ramsay, G. & Cantrell, D. Environmental and metabolic sensors that control T cell biology. Front. Immunol. 6, 99 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Koltsova, E. K. et al. Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis. J. Clin. Investig. 122, 3114–3126 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Geltink, R. I. K., Kyle, R. L. & Pearce, E. L. Unraveling the complex interplay between T cell metabolism and function. Annu. Rev. Immunol. 36, 461–488 (2018).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Howie, D., Ten Bokum, A., Necula, A. S., Cobbold, S. P. & Waldmann, H. The role of lipid metabolism in T lymphocyte differentiation and survival. Front. Immunol. 8, 1949 (2017).

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Kopf, H., de la Rosa, G. M., Howard, O. M. & Chen, X. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int. Immunopharmacol. 7, 1819–1824 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Young, K. E., Flaherty, S., Woodman, K. M., Sharma-Walia, N. & Reynolds, J. M. Fatty acid synthase regulates the pathogenicity of Th17 cells. J. Leukoc. Biol. 102, 1229–1235 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327–1333 (2014).

    CAS  PubMed  Article  Google Scholar 

  75. 75.

    O’Sullivan, D. & Pearce, E. L. Fatty acid synthesis tips the TH17-Treg cell balance. Nat. Med. 20, 1235–1236 (2014).

    PubMed  Article  CAS  Google Scholar 

  76. 76.

    Endo, Y. et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep. 12, 1042–1055 (2015).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Angela, M. et al. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells. Nat. Commun. 7, 13683 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Fan, Y. Y. et al. Remodelling of primary human CD4+ T cell plasma membrane order by n-3 PUFA. Br. J. Nutr. 119, 163–175 (2018).

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Borow, K. M., Nelson, J. R. & Mason, R. P. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis 242, 357–366 (2015).

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Stegemann, C. et al. Comparative lipidomics profiling of human atherosclerotic plaques. Circ. Cardiovasc. Genet. 4, 232–242 (2011).

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Cochran, J. R., Cameron, T. O. & Stern, L. J. The relationship of MHC-peptide binding and T cell activation probed using chemically defined MHC class II oligomers. Immunity 12, 241–250 (2000).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Stentz, F. B. & Kitabchi, A. E. Palmitic acid-induced activation of human T-lymphocytes and aortic endothelial cells with production of insulin receptors, reactive oxygen species, cytokines, and lipid peroxidation. Biochem. Biophys. Res. Commun. 346, 721–726 (2006).

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Moussa, M. et al. In vivo effects of olive oil-based lipid emulsion on lymphocyte activation in rats. Clin. Nutr. 19, 49–54 (2000).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Kew, S. et al. Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Am. J. Clin. Nutr. 79, 674–681 (2004).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Steffen, B. T. et al. Plasma n-3 and n-6 fatty acids are differentially related to carotid plaque and its progression: the multi-ethnic study of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 38, 653–659 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Shipkova, M. & Wieland, E. Surface markers of lymphocyte activation and markers of cell proliferation. Clin. Chim. Acta 413, 1338–1349 (2012).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Haghikia, A. et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817–829 (2015).

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Jayawardena, R., Swarnamali, H., Lanerolle, P. & Ranasinghe, P. Effect of coconut oil on cardio-metabolic risk: a systematic review and meta-analysis of interventional studies. Diabetes Metab. Syndr. 14, 2007–2020 (2020).

    PubMed  Article  Google Scholar 

  90. 90.

    Passos, M. E. et al. Differential effects of palmitoleic acid on human lymphocyte proliferation and function. Lipids Health Dis. 15, 217 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Gorjao, R., Cury-Boaventura, M. F., de Lima, T. M. & Curi, R. Regulation of human lymphocyte proliferation by fatty acids. Cell Biochem. Funct. 25, 305–315 (2007).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Miura, S. et al. Increased proliferative response of lymphocytes from intestinal lymph during long chain fatty acid absorption. Immunology 78, 142–146 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Ioan-Facsinay, A. et al. Adipocyte-derived lipids modulate CD4+ T-cell function. Eur. J. Immunol. 43, 1578–1587 (2013).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Wang, L., Folsom, A. R. & Eckfeldt, J. H. Plasma fatty acid composition and incidence of coronary heart disease in middle aged adults: the Atherosclerosis Risk in Communities (ARIC) study. Nutr. Metab. Cardiovasc. Dis. 13, 256–266 (2003).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Rossetti, R. G., Seiler, C. M., DeLuca, P., Laposata, M. & Zurier, R. B. Oral administration of unsaturated fatty acids: effects on human peripheral blood T lymphocyte proliferation. J. Leukoc. Biol. 62, 438–443 (1997).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Zurier, R. B., Rossetti, R. G., Seller, C. M. & Laposata, M. Human peripheral blood T lymphocyte proliferation after activation of the T cell receptor: effects of unsaturated fatty acids. Prostaglandins Leukot. Essent. Fatty Acids 60, 371–375 (1999).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Fan, Y. Y., Ly, L. H., Barhoumi, R., McMurray, D. N. & Chapkin, R. S. Dietary docosahexaenoic acid suppresses T cell protein kinase C θ lipid raft recruitment and IL-2 production. J. Immunol. 173, 6151–6160 (2004).

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Pompos, L. J. & Fritsche, K. L. Antigen-driven murine CD4+ T lymphocyte proliferation and interleukin-2 production are diminished by dietary (n-3) polyunsaturated fatty acids. J. Nutr. 132, 3293–3300 (2002).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    Ly, L. H., Smith, R., Switzer, K. C., Chapkin, R. S. & McMurray, D. N. Dietary eicosapentaenoic acid modulates CTLA-4 expression in murine CD4+ T-cells. Prostaglandins Leukot. Essent. Fatty Acids 74, 29–37 (2006).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Merzouk, S. A. et al. N-3 polyunsaturated fatty acids modulate in-vitro T cell function in type I diabetic patients. Lipids 43, 485–497 (2008).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Jolly, C. A., Jiang, Y., Chapkin, R. S. & McMurray, D. N. Dietary (n-3) polyunsaturated fatty acids suppress murine lymphoproliferation, interleukin-2 secretion, and the formation of diacylglycerol and ceramide. J. Nutr. 127, 37–43 (1997).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Collison, L. W., Collison, R. E., Murphy, E. J. & Jolly, C. A. Dietary n-3 polyunsaturated fatty acids increase T-lymphocyte phospholipid mass and acyl-CoA binding protein expression. Lipids 40, 81–87 (2005).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    McMurray, D. N., Jolly, C. A. & Chapkin, R. S. Effects of dietary n-3 fatty acids on T cell activation and T cell receptor-mediated signaling in a murine model. J. Infect. Dis. 182, S103–S107 (2000).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Thies, F. et al. Dietary supplementation with γ-linolenic acid or fish oil decreases T lymphocyte proliferation in healthy older humans. J. Nutr. 131, 1918–1927 (2001).

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Ding, L. et al. Eicosapentaenoic acid-enriched phospholipids improve atherosclerosis by mediating cholesterol metabolism. J. Funct. Foods 32, 90–97 (2017).

    CAS  Article  Google Scholar 

  106. 106.

    Erkkila, A. T., Matthan, N. R., Herrington, D. M. & Lichtenstein, A. H. Higher plasma docosahexaenoic acid is associated with reduced progression of coronary atherosclerosis in women with CAD. J. Lipid Res. 47, 2814–2819 (2006).

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Van Noolen, L. et al. Docosahexaenoic acid supplementation modifies fatty acid incorporation in tissues and prevents hypoxia induced-atherosclerosis progression in apolipoprotein-E deficient mice. Prostaglandins Leukot. Essent. Fatty Acids 91, 111–117 (2014).

    PubMed  Article  CAS  Google Scholar 

  108. 108.

    de Oliveira Otto, M. C. et al. Circulating and dietary omega-3 and omega-6 polyunsaturated fatty acids and incidence of CVD in the multi-ethnic study of atherosclerosis. J. Am. Heart Assoc. 2, 000506 (2013).

    Google Scholar 

  109. 109.

    Chang, C. L. & Deckelbaum, R. J. Omega-3 fatty acids: mechanisms underlying “protective effects” in atherosclerosis. Curr. Opin. Lipidol. 24, 345–350 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Block, R. C., Harris, W. S., Reid, K. J., Sands, S. A. & Spertus, J. A. EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls. Atherosclerosis 197, 821–828 (2008).

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Hossein zade, A. Fatty acids effect on T helper differentiation in vitro. Int. J. Food Sci. Nutr. 5, 372–377 (2016).

    CAS  Article  Google Scholar 

  112. 112.

    Bi, X. et al. ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity. J. Clin. Invest. 127, 1757–1771 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Raphael, I., Nalawade, S., Eagar, T. N. & Forsthuber, T. G. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 74, 5–17 (2015).

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Blewett, H. J., Gerdung, C. A., Ruth, M. R., Proctor, S. D. & Field, C. J. Vaccenic acid favourably alters immune function in obese JCR:LA-cp rats. Br. J. Nutr. 102, 526–536 (2009).

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Reynolds, C. M. & Roche, H. M. Conjugated linoleic acid and inflammatory cell signalling. Prostaglandins Leukot. Essent. Fatty Acids 82, 199–204 (2010).

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Jaudszus, A. et al. Vaccenic acid-mediated reduction in cytokine production is independent of c9,t11-CLA in human peripheral blood mononuclear cells. Biochim. Biophys. Acta 1821, 1316–1322 (2012).

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Monk, J. M., Hou, T. Y., Turk, H. F., McMurray, D. N. & Chapkin, R. S. n3 PUFAs reduce mouse CD4+ T-cell ex vivo polarization into Th17 cells. J. Nutr. 143, 1501–1508 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Zhang, P., Smith, R., Chapkin, R. S. & McMurray, D. N. Dietary (n-3) polyunsaturated fatty acids modulate murine Th1/Th2 balance toward the Th2 pole by suppression of Th1 development. J. Nutr. 135, 1745–1751 (2005).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Zhang, P. et al. Dietary fish oil inhibits antigen-specific murine Th1 cell development by suppression of clonal expansion. J. Nutr. 136, 2391–2398 (2006).

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Switzer, K. C., McMurray, D. N., Morris, J. S. & Chapkin, R. S. (n-3) Polyunsaturated fatty acids promote activation-induced cell death in murine T lymphocytes. J. Nutr. 133, 496–503 (2003).

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Robinson, G. A., Waddington, K. E., Pineda-Torra, I. & Jury, E. C. Transcriptional regulation of T-cell lipid metabolism: implications for plasma membrane lipid rafts and T-cell function. Front. Immunol. 8, 1636 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. 122.

    Tan, J. K., McKenzie, C., Marino, E., Macia, L. & Mackay, C. R. Metabolite-sensing G protein-coupled receptors–facilitators of diet-related immune regulation. Annu. Rev. Immunol. 35, 371–402 (2017).

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Wu, G. et al. The efficacy of fish oil in preventing coronary heart disease: A systematic review and meta-analysis. Preprints https://doi.org/10.20944/preprints202009.0497.v1 (2020).

    Article  Google Scholar 

  124. 124.

    Wang, Y., Jacome-Sosa, M. M., Vine, D. F. & Proctor, S. D. Beneficial effects of vaccenic acid on postprandial lipid metabolism and dyslipidemia: impact of natural trans-fats to improve CVD risk. Lipid Technol. 22, 103–106 (2010).

    CAS  Article  Google Scholar 

  125. 125.

    Pettinella, C., Lee, S. H., Cipollone, F. & Blair, I. A. Targeted quantitative analysis of fatty acids in atherosclerotic plaques by high sensitivity liquid chromatography/tandem mass spectrometry. J. Chromatogr. B 850, 168–176 (2007).

    CAS  Article  Google Scholar 

  126. 126.

    Rocha, V. Z. & Libby, P. Obesity, inflammation, and atherosclerosis. Nat. Rev. Cardiol. 6, 399–409 (2009).

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Peng, J., Luo, F., Ruan, G., Peng, R. & Li, X. Hypertriglyceridemia and atherosclerosis. Lipids Health Dis. 16, 233 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  128. 128.

    Bicalho, B., David, F., Rumplel, K., Kindt, E. & Sandra, P. Creating a fatty acid methyl ester database for lipid profiling in a single drop of human blood using high resolution capillary gas chromatography and mass spectrometry. J. Chromatogr. A 1211, 120–128 (2008).

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Maecker, H. T., McCoy, J. P. & Nussenblatt, R. Standardizing immunophenotyping for the Human Immunology Project. Nat. Rev. Immunol. 12, 191–200 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    McLaughlin, B. E. et al. Nine-color flow cytometry for accurate measurement of T cell subsets and cytokine responses. Part I: panel design by an empiric approach. Cytometry A 73A, 400–410 (2008).

    Article  Google Scholar 

  131. 131.

    Leng, S. X. et al. ELISA and multiplex technologies for cytokine measurement in inflammation and aging research. J. Gerontol. A Biol. Sci. Med. Sci. 63, 879–884 (2008).

    PubMed  Article  Google Scholar 

  132. 132.

    Zhou, L., Chong, M. M. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    CAS  PubMed  Article  Google Scholar 

  133. 133.

    Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations*. Annu. Rev. Immunol. 28, 445–489 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Szabo, S. J., Sullivan, B. M., Peng, S. L. & Glimcher, L. H. Molecular mechanisms regulating Th1 immune responses. Annu. Rev. Immunol. 21, 713–758 (2003).

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Sandquist, I. & Kolls, J. Update on regulation and effector functions of Th17 cells. F1000 Res. 7, 205 (2018).

    Article  CAS  Google Scholar 

  136. 136.

    Nakayama, T. et al. Th2 cells in health and disease. Annu. Rev. Immunol. 35, 53–84 (2017).

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Foks, A. C., Lichtman, A. H. & Kuiper, J. Treating atherosclerosis with regulatory T cells. Arterioscler. Thromb. Vasc. Biol. 35, 280–287 (2015).

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Seumois, G. et al. Transcriptional profiling of Th2 cells identifies pathogenic features associated with asthma. J. Immunol. 197, 655–664 (2016).

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Fournier, C. & Where, Do. T. Cells stand in rheumatoid arthritis? Jt. Bone Spine 72, 527–532 (2005).

    Article  Google Scholar 

  140. 140.

    Roep, B. O. The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure. Diabetologia 46, 305–321 (2003).

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Article  CAS  Google Scholar 

  143. 143.

    Warburg, O., Gawehn, K. & Geissler, A. W. Metabolism of leukocytes [German]. Z. Naturforsch. B 13B, 515–516 (1958).

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Michalek, R. D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Cluxton, D., Petrasca, A., Moran, B. & Fletcher, J. M. Differential regulation of human Treg and Th17 cells by fatty acid synthesis and glycolysis. Front. Immunol. 10, 115 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Fullerton, M. D., Steinberg, G. R. & Schertzer, J. D. Immunometabolism of AMPK in insulin resistance and atherosclerosis. Mol. Cell. Endocrinol. 366, 224–234 (2013).

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Maganto-Garcia, E., Tarrio, M. L., Grabie, N., Bu, D. X. & Lichtman, A. H. Dynamic changes in regulatory T cells are linked to levels of diet-induced hypercholesterolemia. Circulation 124, 185–195 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Ketelhuth, D. F. J. et al. Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology. Cardiovasc. Res. 115, 1385–1392 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Gistera, A. & Ketelhuth, D. F. J. Lipid-driven immunometabolic responses in atherosclerosis. Curr. Opin. Lipidol. 29, 375–380 (2018).

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Tomas, L. et al. Altered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques. Eur. Heart J. 39, 2301–2310 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Amersfoort, J. et al. Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells. Cardiovasc. Res. 117, 1309–1324 (2021).

    PubMed  Article  Google Scholar 

  152. 152.

    Delgoffe, G. M. et al. mTOR differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Shi, L. Z. et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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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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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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Nature Reviews Cardiology thanks the anonymous reviewers for their contribution to the peer review of this work.

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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 (2021). https://doi.org/10.1038/s41569-021-00582-9

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