The Role of Lymphocytes in the Pathogenesis of Atherosclerosis: Focus on CD4+ T Cell Subsets

  • Ingrid E. DumitriuEmail author
  • Juan Carlos Kaski


Recent advances in the mechanisms that underlie the pathogenesis of atherosclerosis suggest that chronic inflammation and the immune system actively contribute to the development and aggravation of this disease. Classically, atherosclerosis was mainly attributed to the deposition of lipids (e.g. low-density lipoproteins, LDL) into the intima of medium-sized and large arteries resulting in the progressive thickening of the vessel wall. However, the identification of immune cells such as macrophages and T lymphocytes in atherosclerotic plaques sparked the interest of researchers in understanding the precise roles of these cells in atherosclerosis. Several lines of research in both animal models of atherosclerosis and patients have consolidated the view that the innate and adaptive immune systems are important mediators of the inflammatory process that drives atherosclerosis [1].


Acute Coronary Syndrome Th17 Cell Atherosclerotic Plaque Treg Cell Cell Subset 
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The authors’ research is supported by the British Heart Foundation (grant no. PG/10/50/28434, to IED and JCK) and St. George’s Hospital Charity, London, UK.

Conflict of Interest



  1. 1.
    Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54(23):2129–38.PubMedCrossRefGoogle Scholar
  2. 2.
    Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation. 2005;111(25):3481–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Weber C, Zernecke A, Libby P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nat Rev Immunol. 2008;8(10):802–15.PubMedCrossRefGoogle Scholar
  4. 4.
    Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006;6(7):508–19.PubMedCrossRefGoogle Scholar
  5. 5.
    Newby AC. Metalloproteinases and vulnerable atherosclerotic plaques. Trends Cardiovasc Med. 2007;17(8):253–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011;12(3):204–12.PubMedCrossRefGoogle Scholar
  7. 7.
    Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007;449(7161):419–26.PubMedCrossRefGoogle Scholar
  9. 9.
    Acuto O, Michel F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol. 2003;3(12):939–51.PubMedCrossRefGoogle Scholar
  10. 10.
    Le Gros G et al. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990;172(3):921–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Seder RA et al. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci USA. 1993;90(21):10188–92.PubMedCrossRefGoogle Scholar
  12. 12.
    Bettelli E et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Das J et al. Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med. 2009;206(11):2407–16.PubMedCrossRefGoogle Scholar
  14. 14.
    Mangan PR et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441(7090):231–4.PubMedCrossRefGoogle Scholar
  15. 15.
    Sakaguchi S et al. Regulatory T cells and immune tolerance. Cell. 2008;133(5):775–87.PubMedCrossRefGoogle Scholar
  16. 16.
    Buono C et al. Influence of interferon-gamma on the extent and phenotype of diet-induced atherosclerosis in the LDLR-deficient mouse. Arterioscler Thromb Vasc Biol. 2003;23(3):454–60.PubMedCrossRefGoogle Scholar
  17. 17.
    Gupta S et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997;99(11):2752–61.PubMedCrossRefGoogle Scholar
  18. 18.
    Whitman SC, Ravisankar P, Daugherty A. IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E−/− mice. J Interferon Cytokine Res. 2002;22(6):661–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Whitman SC et al. Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E−/− mice. Am J Pathol. 2000;157(6):1819–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Buono C et al. T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc Natl Acad Sci USA. 2005;102(5):1596–601.PubMedCrossRefGoogle Scholar
  21. 21.
    Niwa T et al. Interferon-gamma produced by bone marrow-derived cells attenuates atherosclerotic lesion formation in LDLR-deficient mice. J Atheroscler Thromb. 2004;11(2):79–87.PubMedCrossRefGoogle Scholar
  22. 22.
    Jonasson L, Holm J, Hansson GK. Smooth muscle cells express Ia antigens during arterial response to injury. Lab Invest. 1988;58(3):310–5.PubMedGoogle Scholar
  23. 23.
    Pober JS et al. Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon. Nature. 1983;305(5936):726–9.PubMedCrossRefGoogle Scholar
  24. 24.
    McLaren JE, Ramji DP. Interferon gamma: a master regulator of atherosclerosis. Cytokine Growth Factor Rev. 2009;20(2):125–35.PubMedCrossRefGoogle Scholar
  25. 25.
    Liuzzo G et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation. 1999;100(21):2135–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Frostegard J et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 1999;145(1):33–43.PubMedCrossRefGoogle Scholar
  27. 27.
    Liuzzo G et al. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation. 2000;101(25):2883–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Namekawa T et al. Functional subsets of CD4 T cells in rheumatoid synovitis. Arthritis Rheum. 1998;41(12):2108–16.PubMedCrossRefGoogle Scholar
  29. 29.
    Nakajima T et al. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation. 2002;105(5):570–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Liuzzo G et al. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol. 2007;50(15):1450–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Giubilato S. Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus. Eur Heart J. 2011;32(10):1214–26.PubMedCrossRefGoogle Scholar
  32. 32.
    Bryl E et al. Modulation of CD28 expression with anti-tumor necrosis factor alpha therapy in rheumatoid arthritis. Arthritis Rheum. 2005;52(10):2996–3003.PubMedCrossRefGoogle Scholar
  33. 33.
    Bryl E et al. Down-regulation of CD28 expression by TNF-alpha. J Immunol. 2001;167(6):3231–8.PubMedGoogle Scholar
  34. 34.
    Zal B, Baboonian C, Kaski JC. Autoreactive CD4+ CD28- T cells and acute coronary syndromes. Arterioscler Thromb Vasc Biol. 2007;27(3):e18; author reply e19.PubMedCrossRefGoogle Scholar
  35. 35.
    Zal B et al. Heat-shock protein 60-reactive CD4+CD28null T cells in patients with acute coronary syndromes. Circulation. 2004;109(10):1230–5.PubMedCrossRefGoogle Scholar
  36. 36.
    Dumitriu IE, Baruah P, Finlayson CJ, Loftus IM, Antunes RF, Lim P, et al. High levels of co-stimulatory receptors OX40 and 4-1BB characterise CD4+CD28null T cells in patients with acute coronary syndrome. Circ Res. 2012;110:857–69.PubMedCrossRefGoogle Scholar
  37. 37.
    Ye P et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med. 2001;194(4):519–27.PubMedCrossRefGoogle Scholar
  38. 38.
    Langrish CL et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201(2):233–40.PubMedCrossRefGoogle Scholar
  39. 39.
    Smith E et al. Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2010;121(15):1746–55.PubMedCrossRefGoogle Scholar
  40. 40.
    van Es T et al. Attenuated atherosclerosis upon IL-17R signaling disruption in LDLr deficient mice. Biochem Biophys Res Commun. 2009;388(2):261–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Ait-Oufella H et al. B cell depletion reduces the development of atherosclerosis in mice. J Exp Med. 2010;207(8):1579–87.PubMedCrossRefGoogle Scholar
  42. 42.
    Eid RE et al. Interleukin-17 and interferon-gamma are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation. 2009;119(10):1424–32.PubMedCrossRefGoogle Scholar
  43. 43.
    Taleb S et al. Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis. J Exp Med. 2009;206(10):2067–77.PubMedCrossRefGoogle Scholar
  44. 44.
    Wan YY. Multi-tasking of helper T cells. Immunology. 2010;130(2):166–71.PubMedCrossRefGoogle Scholar
  45. 45.
    Lloyd CM, Hessel EM. Functions of T cells in asthma: more than just T(H)2 cells. Nat Rev Immunol. 2010;10(12):838–48.PubMedCrossRefGoogle Scholar
  46. 46.
    Schulte S, Sukhova GK, Libby P. Genetically programmed biases in Th1 and Th2 immune responses modulate atherogenesis. Am J Pathol. 2008;172(6):1500–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Davenport P, Tipping PG. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol. 2003;163(3):1117–25.PubMedCrossRefGoogle Scholar
  48. 48.
    King VL, Szilvassy SJ, Daugherty A. Interleukin-4 deficiency decreases atherosclerotic lesion formation in a site-specific manner in female LDL receptor−/− mice. Arterioscler Thromb Vasc Biol. 2002;22(3):456–61.PubMedCrossRefGoogle Scholar
  49. 49.
    Vignali D. How many mechanisms do regulatory T cells need? Eur J Immunol. 2008;38(4):908–11.PubMedCrossRefGoogle Scholar
  50. 50.
    Costantino CM, Baecher-Allan C, Hafler DA. Multiple sclerosis and regulatory T cells. J Clin Immunol. 2008;28(6):697–706.PubMedCrossRefGoogle Scholar
  51. 51.
    Venigalla RK et al. Reduced CD4+, CD25- T cell sensitivity to the suppressive function of CD4+, CD25high, CD127 -/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum. 2008;58(7):2120–30.PubMedCrossRefGoogle Scholar
  52. 52.
    Mallat Z, Ait-Oufella H, Tedgui A. Regulatory T-cell immunity in atherosclerosis. Trends Cardiovasc Med. 2007;17(4):113–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Ait-Oufella H et al. Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med. 2006;12(2):178–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Robertson AK et al. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest. 2003;112(9):1342–50.PubMedGoogle Scholar
  55. 55.
    Sardella G 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.PubMedCrossRefGoogle Scholar
  56. 56.
    Mor A et al. Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J. 2006;27(21):2530–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Ammirati E et al. Circulating CD4+CD25hiCD127lo regulatory T-Cell levels do not reflect the extent or severity of carotid and coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2010;30(9):1832–41.PubMedCrossRefGoogle Scholar
  58. 58.
    Brugaletta S et al. Novel anti-inflammatory effect of statins: reduction of CD4+CD28null T lymphocyte frequency in patients with unstable angina. Heart. 2006;92(2):249–50.PubMedCrossRefGoogle Scholar
  59. 59.
    Mausner-Fainberg K et al. The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis. 2008;197(2):829–39.PubMedCrossRefGoogle Scholar
  60. 60.
    Hurlimann D et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002;106(17):2184–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Rizzello V et al. Modulation of CD4(+)CD28null T lymphocytes by tumor necrosis factor-alpha blockade in patients with unstable angina. Circulation. 2006;113(19):2272–7.PubMedCrossRefGoogle Scholar
  62. 62.
    van Puijvelde GH et al. Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation. 2006;114(18):1968–76.PubMedCrossRefGoogle Scholar
  63. 63.
    van Puijvelde GH 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.PubMedCrossRefGoogle Scholar
  64. 64.
    Mallat Z 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2013

Authors and Affiliations

  1. 1.Division of Clinical Sciences, Cardiovascular Sciences Research CentreSt. George’s University of LondonLondonUK

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