Molecular Medicine

, Volume 21, Supplement 1, pp S13–S18 | Cite as

Once Upon a Time: The Adaptive Immune Response in Atherosclerosis—a Fairy Tale No More

  • Marie Le Borgne
  • Giuseppina Caligiuri
  • Antonino Nicoletti
Invited Review Article


Extensive research has been carried out to decipher the function of the adaptive immune response in atherosclerosis, with the expectation that it will pave the road for the design of immunomodulatory therapies that will prevent or reverse the progression of the disease. All this work has led to the concept that some T- and B-cell subsets are proatherogenic, whereas others are atheroprotective. In addition to the immune response occurring in the spleen and lymph nodes, it has been shown that lymphoid neogenesis takes place in the adventitia of atherosclerotic vessels, leading to the formation of tertiary lymphoid organs where an adaptive immune response can be mounted. Whereas the mechanisms orchestrating the formation of these organs are becoming better understood, their impact on atherosclerosis progression remains unclear. Several potential therapeutic strategies against atherosclerosis, such as protective vaccination against atherosclerosis antigens or inhibiting the activation of proatherogenic B cells, have been proposed based on our improving knowledge of the role of the immune system in atherosclerosis. These strategies have shown success in preclinical studies, giving hope that they will lead to clinical applications.



This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Paris Denis Diderot University, the Région Ile de France (CORDDIM), the Département Hospitalo-Universitaire DHU FIRE, the Fondation de la Recherche Médicale (FRM), the Fondation de France and the Agence Nationale de la Recherche (ANR, grant MI2 ATHLO).


  1. 1.
    Allahverdian S, Chehroudi AC, McManus BM, Abraham T, Francis GA. (2014) Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. Circulation. 129:1551–9.CrossRefGoogle Scholar
  2. 2.
    Hansson GK, Hermansson A. (2011) The immune system in atherosclerosis. Nat. Immunol. 12:204–12.CrossRefGoogle Scholar
  3. 3.
    Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. (1986) Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 6:131–8.CrossRefGoogle Scholar
  4. 4.
    Dansky HM, Charlton SA, Harper MM, Smith JD. (1997) T and B lymphocytes play a minor role in atherosclerotic plaque formation in the apolipoprotein E-deficient mouse. Proc. Natl. Acad. Sci. U. S. A. 94:4642–6.CrossRefGoogle Scholar
  5. 5.
    Zhou X, Nicoletti A, Elhage R, Hansson GK. (2000) Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation. 102:2919–22.CrossRefGoogle Scholar
  6. 6.
    Khallou-Laschet J, et al. (2006) The proatherogenic role of T cells requires cell division and is dependent on the stage of the disease. Arterioscler. Thromb. Vasc. Biol. 26:353–8.CrossRefGoogle Scholar
  7. 7.
    Caligiuri G, et al. (2003) Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol. Med. 9:10–7.CrossRefGoogle Scholar
  8. 8.
    Grabner R, et al. (2009) Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/-mice. J. Exp. Med. 206:233–48.CrossRefGoogle Scholar
  9. 9.
    Guedj K, et al. (2014) M1 macrophages act as LT-betaR-independent lymphoid tissue inducer cells during atherosclerosis-related lymphoid neogenesis. Cardiovasc. Res. 101:434–43.CrossRefGoogle Scholar
  10. 10.
    Houtkamp MA, de Boer OJ, van der Loos CM, van der Wal AC, Becker AE. (2001) Adventitial infiltrates associated with advanced atherosclerotic plaques: structural organization suggests generation of local humoral immune responses. J. Pathol. 193:263–9.CrossRefGoogle Scholar
  11. 11.
    Caligiuri G, Nicoletti A, Poirier B, Hansson GK. (2002) Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. J. Clin. Invest. 109:745–53.CrossRefGoogle Scholar
  12. 12.
    Buono C, et al. (2005) T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses. Proc. Natl. Acad. Sci. U. S. A. 102:1596–601.CrossRefGoogle Scholar
  13. 13.
    Erbel C, et al. (2009) Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice. J. Immunol. 183:8167–75.CrossRefGoogle Scholar
  14. 14.
    Smith E, et al. (2010) Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation. 121:1746–55.CrossRefGoogle Scholar
  15. 15.
    Tupin E, et al. (2004) CD1d-dependent activation of NKT cells aggravates atherosclerosis. J. Exp. Med. 199:417–22.CrossRefGoogle Scholar
  16. 16.
    Binder CJ, et al. (2004) IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis. J. Clin. Invest. 114:427–37.CrossRefGoogle Scholar
  17. 17.
    Ait-Oufella H, et al. (2006) Natural regulatory T cells control the development of atherosclerosis in mice. Nat. Med. 12:178–80.CrossRefGoogle Scholar
  18. 18.
    Klingenberg R, et al. (2013) Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J. Clin. Invest. 123:1323–34.CrossRefGoogle Scholar
  19. 19.
    Ait-Oufella H, et al. (2010) B cell depletion reduces the development of atherosclerosis in mice. J. Exp. Med. 207:1579–87.CrossRefGoogle Scholar
  20. 20.
    Kyaw T, et al. (2010) Conventional B2 B cell depletion ameliorates whereas its adoptive transfer aggravates atherosclerosis. J. Immunol. 185:4410–9.CrossRefGoogle Scholar
  21. 21.
    Binder CJ, et al. (2003) Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat. Med. 9:736–43.CrossRefGoogle Scholar
  22. 22.
    Kyaw T, et al. (2011) B1a B lymphocytes are atheroprotective by secreting natural IgM that increases IgM deposits and reduces necrotic cores in atherosclerotic lesions. Circ. Res. 109:830–40.CrossRefGoogle Scholar
  23. 23.
    Karvonen J, Paivansalo M, Kesaniemi YA, Horkko S. (2003) Immunoglobulin M type of autoantibodies to oxidized low-density lipoprotein has an inverse relation to carotid artery atherosclerosis. Circulation. 108:2107–12.CrossRefGoogle Scholar
  24. 24.
    Tsimikas S, et al. (2007) Relationship of IgG and IgM autoantibodies to oxidized low density lipoprotein with coronary artery disease and cardiovascular events. J. Lipid Res. 48:425–33.CrossRefGoogle Scholar
  25. 25.
    Caligiuri G, et al. (2007) Phosphorylcholinetargeting immunization reduces atherosclerosis. J. Am. Coll. Cardiol. 50:540–6.CrossRefGoogle Scholar
  26. 26.
    Caligiuri G, et al. (2003) Autoreactive antibody repertoire is perturbed in atherosclerotic patients. Lab. Invest. 83:939–47.CrossRefGoogle Scholar
  27. 27.
    Tangye SG, Ma CS, Brink R, Deenick EK. (2013) The good, the bad and the ugly — TFH cells in human health and disease. Nat. Rev. Immunol. 13:412–26.CrossRefGoogle Scholar
  28. 28.
    Kim HJ, Verbinnen B, Tang X, Lu L, Cantor H. (2010) Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 467:328–32.CrossRefGoogle Scholar
  29. 29.
    Clement M, et al. (2015) Control of the Tfh-GC B cell axis by CD8+ Tregs limits atherosclerosis and tertiary lymphoid organ development. Circulation. 131:560–70.CrossRefGoogle Scholar
  30. 30.
    Hu YL, Metz DP, Chung J, Siu G, Zhang M. (2009) B7RP-1 blockade ameliorates autoimmunity through regulation of follicular helper T cells. J. Immunol. 182:1421–8.CrossRefGoogle Scholar
  31. 31.
    Tsiantoulas D, Diehl CJ, Witztum JL, Binder CJ. (2014) B cells and humoral immunity in atherosclerosis. Circ. Res. 114:1743–56.CrossRefGoogle Scholar
  32. 32.
    Foteinos G, Afzal AR, Mandal K, Jahangiri M, Xu Q. (2005) Anti-heat shock protein 60 autoantibodies induce atherosclerosis in apolipoprotein E-deficient mice via endothelial damage. Circulation. 112:1206–13.CrossRefGoogle Scholar
  33. 33.
    Guedj K, et al. (2014) Inflammatory micro-environmental cues of human atherothrombotic arteries confer to vascular smooth muscle cells the capacity to trigger lymphoid neogenesis. PLoS One. 9:e116295.CrossRefGoogle Scholar
  34. 34.
    Thaunat O, et al. (2008) B cell survival in intragraft tertiary lymphoid organs after rituximab therapy. Transplantation. 85:1648–53.CrossRefGoogle Scholar
  35. 35.
    Pitzalis C, Jones GW, Bombardieri M, Jones SA. (2014) Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14:447–62.CrossRefGoogle Scholar
  36. 36.
    van de Pavert SA, Mebius RE. (2010) New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10:664–74.CrossRefGoogle Scholar
  37. 37.
    Lotzer K, et al. (2010) Mouse aorta smooth muscle cells differentiate into lymphoid tissue organizer-like cells on combined tumor necrosis factor receptor-1/lymphotoxin beta-receptor NF-kappaB signaling. Arterioscler. Thromb. Vasc. Biol. 30:395–402.CrossRefGoogle Scholar
  38. 38.
    Thaunat O, et al. (2010) Chronic rejection triggers the development of an aggressive intragraft immune response through recapitulation of lymphoid organogenesis. J. Immunol. 185:717–28.CrossRefGoogle Scholar
  39. 39.
    Brown K, Sacks SH, Wong W. (2011) Tertiary lymphoid organs in renal allografts can be associated with donor-specific tolerance rather than rejection. Eur. J. Immunol. 41:89–96.CrossRefGoogle Scholar
  40. 40.
    Le Texier L, et al. (2011) Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile. American J. Transplant. 11:429–38.CrossRefGoogle Scholar
  41. 41.
    Thaunat O, et al. (2010) Immune responses elicited in tertiary lymphoid tissues display distinctive features. PLoS One. 5:e11398.CrossRefGoogle Scholar
  42. 42.
    Fredrikson GN, et al. (2003) Identification of immune responses against aldehyde-modified pep-tide sequences in apoB associated with cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 23:872–8.CrossRefGoogle Scholar
  43. 43.
    Lahoute C, Herbin O, Mallat Z, Tedgui A. (2011) Adaptive immunity in atherosclerosis: mechanisms and future therapeutic targets. Nat. Rev. Cardiol. 8:348–58.CrossRefGoogle Scholar
  44. 44.
    Newton-Nash DK, Newman PJ. (1999) A new role for platelet-endothelial cell adhesion mole-cule-1 (CD31): inhibition of TCR-mediated signal transduction. J. Immunol. 163:682–8.PubMedGoogle Scholar
  45. 45.
    Clement M, et al. (2015) Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo. J. Autoimmun. 56:23–33.CrossRefGoogle Scholar
  46. 46.
    Clement M, et al. (2014) CD31 is a key coinhibitory receptor in the development of immunogenic dendritic cells. Proc. Natl. Acad. Sci. U. S. A. 111:E1101–10.CrossRefGoogle Scholar
  47. 47.
    Caligiuri G, et al. (2006) Reduced immunoregulatory CD31+ T cells in patients with atherosclerotic abdominal aortic aneurysm. Arterioscler. Thromb. Vasc. Biol. 26:618–23.CrossRefGoogle Scholar
  48. 48.
    Groyer E, et al. (2007) Atheroprotective effect of CD31 receptor globulin through enrichment of circulating regulatory T-cells. J. Am. Coll. Cardiol. 50:344–50.CrossRefGoogle Scholar
  49. 49.
    Fornasa G, et al. (2012) A CD31-derived peptide prevents angiotensin II-induced atherosclerosis progression and aneurysm formation. Cardiovasc. Res. 94:30–7.CrossRefGoogle Scholar

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Authors and Affiliations

  • Marie Le Borgne
    • 1
    • 2
    • 3
  • Giuseppina Caligiuri
    • 1
    • 2
    • 3
  • Antonino Nicoletti
    • 1
    • 2
    • 3
  1. 1.Unité 1148Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Xavier BichatParisFrance
  2. 2.Université Paris Diderot, Sorbonne Paris CitéParisFrance
  3. 3.Département Hospitalo-Universitaire DHU FIREParisFrance

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