Regulatory T-Cells, FoxP3 and Atherosclerosis

  • Michal Entin-Meer
  • Arnon Afek
  • Jacob GeorgeEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 665)


Innate immune responses follow accumulation of modified lipids within the arterial wall thereby influencing atherosclerotic plaque progression. One of the mechanisms evolved in maintaining immunologic self-tolerance involves upregulation of regulatory T-cells, among which the CD4+CD25+ FoxP3+ regulatory T-cells (Treg) are best characterized. The putative important role of Treg in the initiation of atherosclerotic lesions as well as in the progression towards unstable plaques leading to ischemic events, supported by human studies and, indirectly, by murine models. Herein, we summarize the experimental approaches taken in order to study the possible mechanisms of Treg involvement in atherosclerosis as well as the beneficial clinical potential of Treg in stabilizing atherosclerotic plaques.


Treg Cell Atherosclerotic Lesion Unstable Plaque Human Atherosclerotic Plaque Human Atherosclerotic Lesion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Hansson GK. Inflammation, atherosclerosis and coronary artery disease. N Engl J Med 2005; 352(16):1685–95.CrossRefPubMedGoogle Scholar
  2. 2.
    Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006; 6(7):508–19.CrossRefPubMedGoogle Scholar
  3. 3.
    Benagiano M, Azzurri A, Ciervo A et al. T helper type 1 lymphocytes drive inflammation in human atherosclerotic lesions. Proc Natl Acad Sci USA 2003; 100(11):6658–63.CrossRefPubMedGoogle Scholar
  4. 4.
    Frostegård J, Ulfgren AK, Nyberg P et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 1999; 145(1):33–43.CrossRefPubMedGoogle Scholar
  5. 5.
    Hansson GK, Robertson AK, Soderberg-Naucler C. Inflammation and atherosclerosis. Annu Rev Parhol 2006; 1:297–329.CrossRefGoogle Scholar
  6. 6.
    Kleindienst R, Xu Q, Willeit J et al. Immunology of atherosclerosis._Demonstration of heat shock protein 60 expression and T-lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions. Am J Pathol 1993; 142(6):1927–37.PubMedGoogle Scholar
  7. 7.
    Stemme S, Holm J, Hansson GK. T-lymphocytes in human atherosclerotic plaques are memory cells expressing CD45RO and the integrin VLA-1. Arterioscler Thromb 1992; 12(2):206–11.PubMedGoogle Scholar
  8. 8.
    Jonasson L, Holm J, Skalli O et al. Regional accumulations of T-cells, macrophages and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis 1986; 6(2):131–8.PubMedGoogle Scholar
  9. 9.
    van der Wal AC, Das PK, Bentz van de Berg D et al. Atherosclerotic lesions in humans. In situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest 1989; 61(2):166–70.PubMedGoogle Scholar
  10. 10.
    Choi JI, Chung SW, Kang HS et al. Establishment of Porphyromonas gingivalis heat-shock-protein-specific T-cell lines from atherosclerosis patients. J Dent Res 2002; 81(5):344–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Metzler B, Mayr M, Dietrich H et al. Inhibition of arteriosclerosis by T-cell depletion in normocholesterolemic rabbits immunized with heat shock protein 65. Arterioscler Thromb Vasc Biol 1999; 19(8):1905–11.PubMedGoogle Scholar
  12. 12.
    Stemme S, Faber B, Holm J et al. T-lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein. Proc Natl Acad Sci USA 1995; 92(9):3893–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Gotsman I, Gupta R, Lichtman AH. The influence of the regulatory T-lymphocytes on atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27(12):2493–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Fehervari Z, Sakaguchi S. CD4+ Tregs and immune control. J Clin Invest 2004; 114(9):1209–17.PubMedGoogle Scholar
  15. 15.
    Gorelik L, Flavell RA. Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2002; 2(1):46–53.CrossRefPubMedGoogle Scholar
  16. 16.
    Sakaguchi S. Naturally arising CD4+ regulatory T-cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004; 22:531–62.CrossRefPubMedGoogle Scholar
  17. 17.
    Miyara M, Sakaguchi S. Natural regulatory T-cells: mechanisms of suppression. Trends Mol Med 2007; 13(3):108–16.CrossRefPubMedGoogle Scholar
  18. 18.
    Ronchetti S, Zollo O, Bruscoli S et al. GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T-lymphocyte subpopulations. Eur J Immunol 2004; 34(3):613–22.CrossRefPubMedGoogle Scholar
  19. 19.
    Huang CT, Workman CJ, Flies D et al. Role of LAG-3 in regulatory T-cells. Immunity 2004; 21(4):503–13.CrossRefPubMedGoogle Scholar
  20. 20.
    Huehn J, Siegmund K, Lehmann JC et al. Developmental stage, phenotype and migration distinguish naive-and effector/memory-like CD4+ regulatory T-cells. J Exp Med 2004; 199(3):303–13.CrossRefPubMedGoogle Scholar
  21. 21.
    Yurchenko E, Tritt M, Hay V et al. CCR5-dependent homing of naturally occurring CD4+ regulatory T-cells to sites of Leishmania major infection favors pathogen persistence. J Exp Med 2006; 203(11):2451–60.CrossRefPubMedGoogle Scholar
  22. 22.
    Apostolou I, Sarukhan A, Klein L et al. Origin of regulatory T-cells with known specificity for antigen. Nat Immunol 2002; 3(8):756–63.PubMedGoogle Scholar
  23. 23.
    Paust S, Lu L, McCarty N et al. Engagement of B7 on effector T-cells by regulatory T-cells prevents autoimmune disease. Proc Natl Acad Sci USA 2004; 101(28):10398–403.CrossRefPubMedGoogle Scholar
  24. 24.
    Pandiyan P, Zheng L, Ishihara S et al. CD4+CD25+Foxp3+ regulatory T-cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T-cells. Nat Immunol 2007; 8(12):1353–62.CrossRefPubMedGoogle Scholar
  25. 25.
    Collison LW, Workman CJ, Kuo TT et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007; 450(7169):566–9.CrossRefPubMedGoogle Scholar
  26. 26.
    Li MO, Sanjabi S, Flavell RA. Transforming growth factor-beta controls development, homeostasis and tolerance of T-cells by regulatory T-cell-dependent and-independent mechanisms. Immunity 2006; 25(3):455–71.CrossRefPubMedGoogle Scholar
  27. 27.
    Marie C, Liggitt D, Rudensky AY. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T-cell-specific targeting of transforming growth factor-beta receptor. Immunity 2006; 25(3):441–54.CrossRefPubMedGoogle Scholar
  28. 28.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T-cells. Nat Immunol 2003; 4(4):330–6.CrossRefPubMedGoogle Scholar
  29. 29.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T-cell development by the transcription factor Foxp3. Science 2003; 299(5609):1057–61.CrossRefPubMedGoogle Scholar
  30. 30.
    Brunkow ME, Jeffery EW, Hjerrild KA et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001; 27(1):68–73.CrossRefPubMedGoogle Scholar
  31. 31.
    Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 2003; 15(4):430–5.CrossRefPubMedGoogle Scholar
  32. 32.
    Roncador G, Brown PJ, Maestre L et al. Analysis of FOXP3 protein expression in human CD4+CD25+ regulatory T-cells at the single-cell level. Eur J Immunol 2005; 35(6):1681–91.CrossRefPubMedGoogle Scholar
  33. 33.
    Lages CS, Suffia I, Velilla PA et al. Functional regulatory T-cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol 2008; 181(3):1835–48.PubMedGoogle Scholar
  34. 34.
    Zhou X, Jeker LT, Fife BT et al. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med 2008; 205(9):1983–91.CrossRefPubMedGoogle Scholar
  35. 35.
    Curiel TJ. Regulatory T-cell development: is Foxp3 the decider? Nat Med 2007; 13(3):250–3.CrossRefPubMedGoogle Scholar
  36. 36.
    George J, Shoenfeld Y, Harats D._The involvement of beta2-glycoprotein I (beta2-GPI) in human and murine atherosclerosis. J Autoimmun 1999; 13(1):57–60.CrossRefPubMedGoogle Scholar
  37. 37.
    Palinski W, Rosenfeld ME, Ylä-Herttuala S et al. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci USA 1989; 86(4):1372–6.CrossRefPubMedGoogle Scholar
  38. 38.
    Xu Q, Luef G, Weimann S et al. Staining of endothelial cells and macrophages in atherosclerotic lesions with human heat-shock protein-reactive antisera. Arterioscler Thromb 1993; 13(12):1763–9.PubMedGoogle Scholar
  39. 39.
    George J, Afek A, Gilburd B et al. Cellular and humoral immune responses to heat shock protein 65 are both involved in promoting fatty-streak formation in LDL-receptor deficient mice. J Am Coll Cardiol 2001; 38(3):900–5.CrossRefPubMedGoogle Scholar
  40. 40.
    George J, Harats D, Gilburd B et al. Adoptive transfer of beta(2)-glycoprotein I-reactive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice. Circulation 2000; 102(15):1822–7.PubMedGoogle Scholar
  41. 41.
    Zhou X, Nicoletti A, Elhage R et al. Transfer of CD4(+) T-cells aggravates atherosclerosis in immuno-deficient apolipoprotein E knockout mice. Circulation 2000; 102(24):2919–22.PubMedGoogle Scholar
  42. 42.
    Harats D, Yacov N, Gilburd B et al. Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosis-induced and high-fat-diet-driven atherosclerotic lesions. J Am Coll Cardiol 2002; 40(7):1333–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Maron R, Sukhova G, Faria AM et al. Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 2002; 106(13):1708–15.CrossRefPubMedGoogle Scholar
  44. 44.
    van Puijvelde GH, van Es T, van Wanrooij EJ et al. Induction of oral tolerance to HSP60 or an HSP60-peptide activates T-cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 2007; 27(12):2677–83.CrossRefPubMedGoogle Scholar
  45. 45.
    Almeida AR, Legrand N, Papiernik M et al. Homeostasis of peripheral CD4+ T-cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T-cell numbers. J Immunol 2002; 169(9):4850–60.PubMedGoogle Scholar
  46. 46.
    Zhang SH, Reddick RL, Piedrahita JA et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 1992; 258(5081):468–71.CrossRefPubMedGoogle Scholar
  47. 47.
    Mallat Z, Gojova A, Brun V et al. Induction of a regulatory T-cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation 2003; 108(10):1232–7.CrossRefPubMedGoogle Scholar
  48. 48.
    Stoll G, Bendszus M. Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 2006; 37(7):1923–32.CrossRefPubMedGoogle Scholar
  49. 49.
    Ishibashi S, Goldstein JL, Brown MS et al. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest 1994; 93(5):1885–93.CrossRefPubMedGoogle Scholar
  50. 50.
    Ait-Oufella H, Salomon BL, Potteaux S et al. Natural regulatory T-cells control the development of atherosclerosis in mice. Nat Med 2006; 12(2):178–80.CrossRefPubMedGoogle Scholar
  51. 51.
    Mor A, Planer D, Luboshits G et al. Role of naturally occurring CD4+ CD25+ regulatory T-cells in experimental atherosclerosis. Arterioscler Thromb Vase Biol 2007; 27(4):893–900.CrossRefGoogle Scholar
  52. 52.
    Buono C, Pang H, Uchida Y et al. B7-1/B7-2 costimulation regulates plaque antigen-specific T-cell responses and atherogenesis in low-density lipoprotein receptor-deficient mice. Circulation 2004; 109(16):2009–15.CrossRefPubMedGoogle Scholar
  53. 53.
    Gotsman I, Grabie N, Gupta R et al. Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule. Circulation 2006; 114(19):2047–55.CrossRefPubMedGoogle Scholar
  54. 54.
    Zhang L, Peppel K, Sivashanmugam P et al. Expression of tumor necrosis factor receptor-1 in arterial wall cells promotes atherosclerosis. Arterioscler Thromb Vase Biol 2007; 27(5):1087–94.Google Scholar
  55. 55.
    Ben-Shoshan J, Maysel-Auslender S, Mor A et al. Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible facror-1alpha. Eur J Immunol 2008; 38(9):2412–8.CrossRefPubMedGoogle Scholar
  56. 56.
    Schwartz SM, Galis ZS, Rosenfeld M E et al. Plaque rupture in humans and mice. Arterioscler Thromb Vase Biol 2007; 27(4):705–13.CrossRefGoogle Scholar
  57. 57.
    Naghavi M, Libby P, Falk E et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II. Circulation 2003; 108(15):1772–8.CrossRefPubMedGoogle Scholar
  58. 58.
    Naghavi M, Libby P, Falk E et al. From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003; 108(14):1664–72.CrossRefPubMedGoogle Scholar
  59. 59.
    Hosono M, de Boer OJ, van der Wal AC et al. Increased expression of T-cell activation markers (CD25, CD26, CD40L and CD69) in atherectomy specimens of patients with unstable angina and acute myocardial infarction. Atherosclerosis 2003; 168(1):73–80.CrossRefPubMedGoogle Scholar
  60. 60.
    van der Wal AC, Piek JJ, de Boer OJ et al. Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes. Heart 1998; 80( 1):14–8.PubMedGoogle Scholar
  61. 61.
    Mor A, Luboshits G, Planer D et al. Altered status of CD4(+)CD25(+) regulatory T-cells in patients with acute coronary syndromes. Eur Heart J 2006; 27(21):2530–7.CrossRefPubMedGoogle Scholar
  62. 62.
    Sardella G, De Luca L, Francavilla V et al. Frequency of naturally-occurring regulatory T-cells is reduced in patients with ST-segment elevation myocardial infarction. Thromb Res 2007; 120(4):631–4.CrossRefPubMedGoogle Scholar
  63. 63.
    de Boer OJ, van der Meer JJ, Teeling P et al. Low numbers of FOXP3 positive regulatory T-cells are present in all developmental stages of human atherosclerotic lesions. PLoS ONE 2007; 2(1):e779.CrossRefGoogle Scholar
  64. 64.
    De Palma R, Del Galdo F, Abbate G et al. Patients with acute coronary syndrome show oligoclonal T-cell recruitment within unstable plaque: evidence for a local, intracoronary immunologic mechanism. Circulation 2006; 113(5):640–6.CrossRefPubMedGoogle Scholar
  65. 65.
    Shevach EM._From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006; 25(2):195–201.CrossRefPubMedGoogle Scholar
  66. 66.
    Mausner-Fainberg K, Luboshits G, Mor A et al. The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T-cells. Atherosclerosis 2008; 197(2):829–39.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer+Business Media 2009

Authors and Affiliations

  1. 1.Department of CardiologyTel Aviv Sourasky Medical CenterTel AvivIsrael
  2. 2.Institute of Pathology Sheba Medical CenterTel Aviv UniversityTel AvivIsrael

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