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.
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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Schaftenaar, F., Frodermann, V., Kuiper, J. & Lutgens, E. Atherosclerosis: the interplay between lipids and immune cells. Curr. Opin. Lipidol. 27, 209–215 (2016).
Barquera, S. et al. Global overview of the epidemiology of atherosclerotic cardiovascular disease. Arch. Med. Res. 46, 328–338 (2015).
Brown, M. S. & Goldstein, J. L. How LDL receptors influence cholesterol and atherosclerosis. Sci. Am. 251, 58–69 (1984).
Brown, M. S. & Goldstein, J. L. A receptor-mediated pathway for cholesterol homeostasis. Science 232, 34–47 (1986).
Tabas, I. & Lichtman, A. H. Monocyte-macrophages and T cells in atherosclerosis. Immunity 47, 621–634 (2017).
Hansson, G. K., Holm, J. & Jonasson, L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am. J. Pathol. 135, 169–175 (1989).
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).
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).
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).
Ketelhuth, D. F. & Hansson, G. K. Adaptive response of T and B cells in atherosclerosis. Circ. Res. 118, 668–678 (2016).
Aukrust, P. et al. The complex role of T-cell-based immunity in atherosclerosis. Curr. Atheroscler. Rep. 10, 236–243 (2008).
Saigusa, R., Winkels, H. & Ley, K. T cell subsets and functions in atherosclerosis. Nat. Rev. Cardiol. 17, 387–401 (2020).
Cochain, C. & Zernecke, A. Protective and pathogenic roles of CD8+ T cells in atherosclerosis. Basic Res. Cardiol. 111, 71 (2016).
van Duijn, J., Kuiper, J. & Slutter, B. The many faces of CD8+ T cells in atherosclerosis. Curr. Opin. Lipidol. 29, 411–416 (2018).
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).
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).
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).
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).
Fernandez, D. M. et al. Single-cell immune landscape of human atherosclerotic plaques. Nat. Med. 25, 1576–1588 (2019).
Depuydt, M. A. C. et al. Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics. Circ. Res. 127, 1437–1455 (2020).
Zernecke, A. et al. Meta-analysis of leukocyte diversity in atherosclerotic mouse aortas. Circ. Res. 127, 402–426 (2020).
Williams, J. W. et al. Single cell RNA sequencing in atherosclerosis research. Circ. Res. 126, 1112–1126 (2020).
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).
Stemme, S. et al. T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc. Natl Acad. Sci. USA 92, 3893–3897 (1995).
Wolf, D. et al. Pathogenic autoimmunity in atherosclerosis evolves from initially protective apolipoprotein B100-reactive CD4(+) T-regulatory cells. Circulation 142, 1279–1293 (2020).
van Puijvelde, G. H. et al. Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation 114, 1968–1976 (2006).
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).
Tse, K. et al. Atheroprotective vaccination with MHC-II restricted peptides from ApoB-100. Front. Immunol. 4, 493 (2013).
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).
McNamara, D. J. Dietary cholesterol and atherosclerosis. Biochim. Biophys. Acta 1529, 310–320 (2000).
Talayero, B. G. & Sacks, F. M. The role of triglycerides in atherosclerosis. Curr. Cardiol. Rep. 13, 544–552 (2011).
Dron, J. S. & Hegele, R. A. Genetics of triglycerides and the risk of atherosclerosis. Curr. Atheroscler. Rep. 19, 31 (2017).
Nordestgaard, B. G. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease new insights from epidemiology, genetics, and biology. Circ. Res. 118, 547–563 (2016).
Keech, A. C. & Jenkins, A. J. Triglyceride-lowering trials. Curr. Opin. Lipidol. 28, 477–487 (2017).
Salakhutdinov, N. F. & Laev, S. S. Triglyceride-lowering agents. Bioorg. Med. Chem. 22, 3551–3564 (2014).
Budoff, M. Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. Am. J. Cardiol. 118, 138–145 (2016).
Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).
Bhatt, D. L. et al. Effects of icosapent ethyl on total ischemic events from REDUCE-IT. J. Am. Coll. Cardiol. 73, 2791–2802 (2019).
Kersten, S. Triglyceride metabolism under attack. Cell Metab. 25, 1209–1210 (2017).
Kersten, S. Physiological regulation of lipoprotein lipase. Biochim. Biophys. Acta 1841, 919–933 (2014).
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).
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).
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).
Marangoni, F. et al. Dietary linoleic acid and human health: focus on cardiovascular and cardiometabolic effects. Atherosclerosis 292, 90–98 (2020).
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).
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).
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).
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).
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).
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).
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).
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).
Spigoni, V. et al. Stearic acid at physiologic concentrations induces in vitro lipotoxicity in circulating angiogenic cells. Atherosclerosis 265, 162–171 (2017).
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).
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).
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).
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).
Ghoshal, S., Witta, J., Zhong, J., de Villiers, W. & Eckhardt, E. Chylomicrons promote intestinal absorption of lipopolysaccharides. J. Lipid Res. 50, 90–97 (2009).
Randolph, G. J. & Miller, N. E. Lymphatic transport of high-density lipoproteins and chylomicrons. J. Clin. Invest. 124, 929–935 (2014).
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).
Chowdhury, R. et al. Association of dietary, circulating, and supplement fatty acids with coronary risk. Ann. Intern. Med. 160, 398–406 (2014).
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).
Chapman, N. M., Boothby, M. R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20, 55–70 (2020).
Sprent, J. & Surh, C. D. Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat. Immunol. 12, 478–484 (2011).
Smith-Garvin, J. E., Koretzky, G. A. & Jordan, M. S. T cell activation. Annu. Rev. Immunol. 27, 591–619 (2009).
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).
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).
Ramsay, G. & Cantrell, D. Environmental and metabolic sensors that control T cell biology. Front. Immunol. 6, 99 (2015).
Koltsova, E. K. et al. Dynamic T cell-APC interactions sustain chronic inflammation in atherosclerosis. J. Clin. Investig. 122, 3114–3126 (2012).
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).
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).
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).
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).
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).
O’Sullivan, D. & Pearce, E. L. Fatty acid synthesis tips the TH17-Treg cell balance. Nat. Med. 20, 1235–1236 (2014).
Endo, Y. et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep. 12, 1042–1055 (2015).
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).
Ma, C. et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531, 253–257 (2016).
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).
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).
Stegemann, C. et al. Comparative lipidomics profiling of human atherosclerotic plaques. Circ. Cardiovasc. Genet. 4, 232–242 (2011).
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).
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).
Moussa, M. et al. In vivo effects of olive oil-based lipid emulsion on lymphocyte activation in rats. Clin. Nutr. 19, 49–54 (2000).
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).
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).
Shipkova, M. & Wieland, E. Surface markers of lymphocyte activation and markers of cell proliferation. Clin. Chim. Acta 413, 1338–1349 (2012).
Haghikia, A. et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817–829 (2015).
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).
Passos, M. E. et al. Differential effects of palmitoleic acid on human lymphocyte proliferation and function. Lipids Health Dis. 15, 217 (2016).
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).
Miura, S. et al. Increased proliferative response of lymphocytes from intestinal lymph during long chain fatty acid absorption. Immunology 78, 142–146 (1993).
Ioan-Facsinay, A. et al. Adipocyte-derived lipids modulate CD4+ T-cell function. Eur. J. Immunol. 43, 1578–1587 (2013).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Ding, L. et al. Eicosapentaenoic acid-enriched phospholipids improve atherosclerosis by mediating cholesterol metabolism. J. Funct. Foods 32, 90–97 (2017).
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).
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).
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).
Chang, C. L. & Deckelbaum, R. J. Omega-3 fatty acids: mechanisms underlying “protective effects” in atherosclerosis. Curr. Opin. Lipidol. 24, 345–350 (2013).
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).
Hossein zade, A. Fatty acids effect on T helper differentiation in vitro. Int. J. Food Sci. Nutr. 5, 372–377 (2016).
Bi, X. et al. ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity. J. Clin. Invest. 127, 1757–1771 (2017).
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).
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).
Reynolds, C. M. & Roche, H. M. Conjugated linoleic acid and inflammatory cell signalling. Prostaglandins Leukot. Essent. Fatty Acids 82, 199–204 (2010).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Rocha, V. Z. & Libby, P. Obesity, inflammation, and atherosclerosis. Nat. Rev. Cardiol. 6, 399–409 (2009).
Peng, J., Luo, F., Ruan, G., Peng, R. & Li, X. Hypertriglyceridemia and atherosclerosis. Lipids Health Dis. 16, 233 (2017).
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).
Maecker, H. T., McCoy, J. P. & Nussenblatt, R. Standardizing immunophenotyping for the Human Immunology Project. Nat. Rev. Immunol. 12, 191–200 (2012).
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).
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).
Zhou, L., Chong, M. M. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).
Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations*. Annu. Rev. Immunol. 28, 445–489 (2010).
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).
Sandquist, I. & Kolls, J. Update on regulation and effector functions of Th17 cells. F1000 Res. 7, 205 (2018).
Nakayama, T. et al. Th2 cells in health and disease. Annu. Rev. Immunol. 35, 53–84 (2017).
Foks, A. C., Lichtman, A. H. & Kuiper, J. Treating atherosclerosis with regulatory T cells. Arterioscler. Thromb. Vasc. Biol. 35, 280–287 (2015).
Seumois, G. et al. Transcriptional profiling of Th2 cells identifies pathogenic features associated with asthma. J. Immunol. 197, 655–664 (2016).
Fournier, C. & Where, Do. T. Cells stand in rheumatoid arthritis? Jt. Bone Spine 72, 527–532 (2005).
Roep, B. O. The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure. Diabetologia 46, 305–321 (2003).
MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259–283 (2013).
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).
Warburg, O., Gawehn, K. & Geissler, A. W. Metabolism of leukocytes [German]. Z. Naturforsch. B 13B, 515–516 (1958).
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).
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).
Fullerton, M. D., Steinberg, G. R. & Schertzer, J. D. Immunometabolism of AMPK in insulin resistance and atherosclerosis. Mol. Cell. Endocrinol. 366, 224–234 (2013).
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).
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).
Gistera, A. & Ketelhuth, D. F. J. Lipid-driven immunometabolic responses in atherosclerosis. Curr. Opin. Lipidol. 29, 375–380 (2018).
Tomas, L. et al. Altered metabolism distinguishes high-risk from stable carotid atherosclerotic plaques. Eur. Heart J. 39, 2301–2310 (2018).
Amersfoort, J. et al. Diet-induced dyslipidemia induces metabolic and migratory adaptations in regulatory T cells. Cardiovasc. Res. 117, 1309–1324 (2021).
Delgoffe, G. M. et al. mTOR differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).
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).
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).
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).
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.
The authors declare no competing interests.
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- 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.
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