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Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1099-1101
doi: 10.1161/hq0701.093687
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:1099.)
© 2001 American Heart Association, Inc.

Editorial

Plaque T-Cell Activity

Not So Specific?

Sten Stemme

From the Cardiovascular Research Unit, Center for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.

Correspondence to Sten Stemme, MD, PhD, Cardiovascular Research Unit, Center for Molecular Medicine L8:03, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail sten.stemme{at}cmm.ki.se

The notion that atherosclerosis has an inflammatory component was already proposed in the 19th century by Virchow, on the basis of light microscopic analysis of human plaques. The hypothesis was later supported by electron microscopic studies and was confirmed when immunohistochemical analysis revealed that the CD14+ macrophage indeed was the major cell type in the plaque.1 2 More surprising was the finding that T lymphocytes were also present in substantial numbers in human plaques.1 The presence of cellular representatives of the specific, adaptive immune system in this disease has since then inspired a whole area of research, and our knowledge has certainly grown. T lymphocytes are designed to perform effector functions after activation by a specific antigen via the T-cell receptor. A first obvious question was, therefore, what these antigen-specific cells might be reactive to. Are there atherosclerosis-related antigens taking part in atherogenesis? This inquiry constitutes something of a "needle-in-a-haystack" problem, and the question of clonal composition is easier to address. The presence of clonal T-cell expansions would suggest reactivity to a limited number of antigens in early experimental atherosclerosis.3 More advanced human plaques, however, demonstrate a polyclonal T-cell composition.4 5 This characteristic does not constitute evidence that T cells are "nonspecific" (ie, are carrying reactivities not related to atherosclerosis), but it does suggest that no single antigen reactivity dominates the T-cell population. This result in itself is not surprising, because it is known from other inflammatory conditions, with known eliciting antigens, that antigen-specific cells in general constitute a minority of all infiltrating T cells. Furthermore, very few data support the concept of antigen-specific T-cell recruitment, suggesting instead that T-cell infiltrates arise by predominantly non–antigen-specific recruitment, which may be followed by local, clonal, antigen-driven proliferation. Indeed, several studies have by now demonstrated the presence of T cells in atherosclerotic plaques with specificity to atherosclerosis-related antigens, such as oxidized LDL,6 heat shock proteins,7 and Chlamydia pneumoniae.8 9 10 Many studies in recent years have demonstrated pronounced effects on experimental atherosclerosis by immune system modulation, such as immunization or different approaches to immunosuppression.11 12 13 14 15 16 17 This in line with the current working hypothesis stating that antigen-specific T-cell activation is an important component of the atherosclerotic process.

In the present issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Houtkamp et al18 present data that suggest that antigen-specific activation may not be the only way to induce T-cell activity in atherosclerosis. The authors demonstrated the presence of interleukin-15 (IL-15), a cytokine with the potential to trigger T-cell activation and proliferation in the absence of specific T-cell receptor engagement, in human atherosclerotic plaques. Analyzing human carotid and coronary arteries by in situ hybridization, these authors detected IL-15 mRNA in lipid-rich plaques, predominantly colocalizing with CD68-reactive macrophages. Immunohistochemical staining showed IL-15 protein reactivity in the same areas while surrounding T cells were negative. Independently, by a gene expression array technique, we recently detected this cytokine ourselves in mouse atherosclerotic plaques (Wuttge et al19 ). Aortas of apo E-/- mice showed elevated levels of IL-15 mRNA, by gene array hybridization, after 10 and 20 weeks of consuming a cholesterol-enriched diet compared with aortas from normal C57BL6 mice. The result was confirmed by quantitative polymerase chain reaction and at the protein level by immunohistochemistry. Similar to Houtkamp et al,18 we could also demonstrate IL-15 protein in human lesions. Because IL-15 stands out among cytokines by the strong posttranscriptional regulation of its expression, demonstration of the protein product is crucial.

What then, are the properties and actions of IL-15? IL-15 was discovered as a factor stimulating T-cell proliferation in a manner similar to that of the T-cell growth factor IL-2. This resemblance can be explained by the fact that IL-15 acts on the same family of cytokine receptors, even though it has no sequence homology to IL-2. The 2 cytokines share a number of biological activities, including stimulation of proliferation of activated CD4+, CD8+ T cells.20 Collagen-induced arthritis and the delayed-type hypersensitivity reaction are inhibited by blocking IL-15 receptor ligation, thus illustrating the importance of IL-15 in antigen-mediated inflammation in vivo.21 22 Interestingly, as pointed out by Houtkamp et al18 in the present article, in addition to its capacity to promote antigen-induced T-cell proliferation, IL-15 has been shown to induce T-cell activation independent of T-cell receptor stimulation.23 24 IL-15 also has potent proinflammatory properties, inducing the expression of several proinflammatory and chemotactic mediators in macrophages in vitro25 26 and of tumor necrosis factor-{alpha}, IL-1, and interferon alfa (IFN-{alpha}) in vivo.27 Importantly, IL-15 is a strong chemoattractant for T cells.28

IL-15 is constitutively expressed in a wide variety of cells, such as monocytes, skeletal muscle cells, endothelial cells, epithelial cells, and fibroblasts20 29 but not by T cells.30 IL-15 has been detected in inflammatory conditions such as rheumatoid arthritis.31 Inflammatory stimuli such as bacterial lipopolysaccharide and IFN-{alpha} upregulate IL-15 mRNA in freshly isolated monocytes, and nuclear factor-{kappa}B (NF-{kappa}B) and interferon regulatory factor motifs are conserved in the 5'-flanking region of the IL-15 gene in both humans and mice.32 33 How may the activities of IL-15 be involved in atherogenesis?

"Naive" T cells, ie, T cells that since their release from the thymus have never been exposed to their antigens, are basically inert cells. At their first encounter with their specific antigen, they are activated, proliferate, and perform effector functions such as cytotoxicity and cytokine secretion. When antigen challenge recedes, the cells turn into memory T cells. These cells are characterized by their cell surface protein expression34 and are poised for vigorous response to a renewed antigen challenge.35 In fact, a majority of plaque T cells are such memory cells.36 Non–antigen-specific activation of memory T cells would represent a waste of specificity and is potentially dangerous. Yet in recent years, several examples of non–antigen-dependent T-cell activation have been presented.23 24 37 The demonstration of cytokines with this potential in atherosclerosis is an important finding and suggests that cytokine secretion by the large number of memory "bystander" T cells may significantly contribute to local inflammatory activity.

Furthermore, Houtkamp et al18 in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology demonstrate colocalization of IL-15–positive macrophages and immunoreactive oxidized LDL. Because oxidized LDL may activate NF-{kappa}B, it seems likely that oxidized LDL and other proinflammatory components of the forming lesion could induce IL-15 secretion. CD40 ligation may also promote IL-15 secretion,38 and this event could be particularly important in atherosclerotic lesions, in which CD40 as well as its ligand CD40L are abundantly expressed on vascular as well as immune cells.39 IL-15 induced through either of these mechanisms could in turn exacerbate local inflammation by activating proinflammatory CD4+CD45RO+ memory T cells.36

It has recently been shown that IL-15 is involved in the recruitment of activated memory T cells to sites of inflammation by a novel, recently described mechanism.29 40 IL-15 induces the expression of hyaluronan by endothelial cells, thereby promoting binding to the hyaluronan receptor CD44 on activated T cells.41 This event is followed by secondary CD44/VLA-4–mediated adhesion that leads to extravasation of the activated T cells.42 The potential importance of this mechanism in immune-mediated inflammatory disorders is illustrated by the fact that antibodies to CD44 and integrin-{alpha}4 prevented experimental autoimmune encephalomyelitis induced by the transfer of myelin basic protein–specific T cells in rats.43 CD44 is expressed by memory T cells, the predominating phenotype among plaque T cells,36 suggesting that this recruitment pathway may be important in atherosclerosis.

In conclusion, IL-15 is a potent proinflammatory cytokine with several proinflammatory activities, including the capacity to recruit T cells and to antigen-independently induce T-cell cytokine secretion. Hopefully, further investigation will reveal whether either of these mechanisms, or both, indeed constitute the driving force in atherogenesis.

References

  1. Jonasson L, Holm J, Skalli O, Bondjers G, Hansson GK. Regional accumulations of T cells, macrophages, and smooth muscle cells in the human atherosclerotic plaque. Arteriosclerosis. 1986;6:131–138.[Abstract/Free Full Text]
  2. Gown AM, Tsukada T, Ross R. Human atherosclerosis, II: immunocytochemical analysis of the cellular composition of human atherosclerotic lesions. Am J Pathol. 1986;125:191–207.[Abstract]
  3. Paulsson G, Zhou X, Tornquist E, Hansson GK. Oligoclonal T cell expansions in atherosclerotic lesions of apolipoprotein E–deficient mice. Arterioscler Thromb Vasc Biol. 2000;20:10–17.[Abstract/Free Full Text]
  4. Stemme S, Rymo L, Hansson GK. Polyclonal origin of T lymphocytes in human atherosclerotic plaques. Lab Invest. 1991;65:654–660.[Medline] [Order article via Infotrieve]
  5. Swanson S, Rosenzweig A, Seidman JG, Libby P. Diversity of T-cell antigen receptor Vb gene utilization in advanced human atheroma. Arterioscler Thromb. 1994;14:1210–1214.[Abstract/Free Full Text]
  6. Stemme S, Faber B, Holm J, Wiklund O, Witztum JL, Hansson GK. T lymphocytes from human atherosclerotic plaques recognize oxidized LDL. Proc Natl Acad Sci U S A. 1995;92:3893–3897.[Abstract/Free Full Text]
  7. Xu Q, Kleindienst R, Waitz W, Dietrich H, Wick G. Increased expression of heat shock protein 65 coincides with a population of infiltrating T lymphocytes in atherosclerotic lesions of rabbits specifically responding to heat shock protein 65. J Clin Invest. 1993;91:2693–2702.
  8. de Boer OJ, van der Wal AC, Houtkamp MA, Ossewaarde JM, Teeling P, Becker AE. Unstable atherosclerotic plaques contain T-cells that respond to Chlamydia pneumoniae. Cardiovasc Res. 2000;48:402–408.[Abstract/Free Full Text]
  9. Curry AJ, Portig I, Goodall JC, Kirkpatrick PJ, Gaston JS. T lymphocyte lines isolated from atheromatous plaque contain cells capable of responding to Chlamydia antigens. Clin Exp Immunol. 2000;121:261–269.[Medline] [Order article via Infotrieve]
  10. Mosorin M, Surcel HM, Laurila A, Lehtinen M, Karttunen R, Juvonen J, Paavonen J, Morrison RP, Saikku P, Juvonen T. Detection of Chlamydia pneumoniae–reactive T lymphocytes in human atherosclerotic plaques of carotid artery. Arterioscler Thromb Vasc Biol. 2000;20:1061–1067.[Abstract/Free Full Text]
  11. Palinski W, Miller E, Witztum JL. Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci U S A. 1995;92:821–825.[Abstract/Free Full Text]
  12. Ameli S, Hultgardh-Nilsson A, Regnstrom J, Calara F, Yano J, Cercek B, Shah PK, Nilsson J. Effect of immunization with homologous LDL and oxidized LDL on early atherosclerosis in hypercholesterolemic rabbits. Arterioscler Thromb Vasc Biol. 1996;16:1074–1079.[Abstract/Free Full Text]
  13. Xu Q, Kleindienst R, Schett G, Waitz W, Jindal S, Gupta RS, Dietrich H, Wick G. Regression of arteriosclerotic lesions induced by immunization with heat shock protein 65-containing material in normocholesterolemic, but not hypercholesterolemic, rabbits. Atherosclerosis. 1996;123:145–155.[Medline] [Order article via Infotrieve]
  14. Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK. Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. J Clin Invest. 1998;102:910–918.[Medline] [Order article via Infotrieve]
  15. George J, Afek A, Gilburd B, Levkovitz H, Shaish A, Goldberg I, Kopolovic Y, Wick G, Shoenfeld Y, Harats D. Hyperimmunization of apo-E-deficient mice with homologous malondialdehyde low-density lipoprotein suppresses early atherogenesis. Atherosclerosis. 1998;138:147–152.[Medline] [Order article via Infotrieve]
  16. Freigang S, Horkko S, Miller E, Witztum JL, Palinski W. Immunization of LDL receptor–deficient mice with homologous malondialdehyde-modified and native LDL reduces progression of atherosclerosis by mechanisms other than induction of high titers of antibodies to oxidative neoepitopes. Arterioscler Thromb Vasc Biol. 1998;18:1972–1982.[Abstract/Free Full Text]
  17. Hansson GK. Atherosclerosis: cell biology and lipoproteins. Curr Opin Lipidol. 1998;9:73–75.[Medline] [Order article via Infotrieve]
  18. Houtkamp MA, van der Wal AC, de Boer OJ, van der Loos CM, de Boer PAJ, Moorman AFM, Becker AE. Interleukin-15 expression in atherosclerotic plaques: an alternative pathway for T-cell activation in atherosclerosis? Arterioscler Thromb Vasc Biol. 2001;21:1208–1213.[Abstract/Free Full Text]
  19. Wuttge et al. Title. Am J Pathol. In press.
  20. Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M, et al. Cloning of a T cell growth factor that interacts with the ß-chain of the interleukin-2 receptor. Science. 1994;264:965–968.[Abstract/Free Full Text]
  21. Kim YS, Maslinski W, Zheng XX, Stevens AC, Li XC, Tesch GH, Kelley VR, Strom TB. Targeting the IL-15 receptor with an antagonist IL-15 mutant/Fc {gamma}2a protein blocks delayed-type hypersensitivity. J Immunol. 1998;160:5742–5748.[Abstract/Free Full Text]
  22. Ruchatz H, Leung BP, Wei XQ, McInnes IB, Liew FY. Soluble IL-15 receptor {alpha}-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J Immunol. 1998;160:5654–5660.[Abstract/Free Full Text]
  23. McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-{alpha} production in rheumatoid arthritis [see comments]. Nat Med. 1997;3:189–195.[Medline] [Order article via Infotrieve]
  24. Avice MN, Demeure CE, Delespesse G, Rubio M, Armant M, Sarfati M. IL-15 promotes IL-12 production by human monocytes via T cell-dependent contact and may contribute to IL-12-mediated IFN-{gamma} secretion by CD4+ T cells in the absence of TCR ligation. J Immunol. 1998;161:3408–3415.[Abstract/Free Full Text]
  25. Badolato R, Ponzi AN, Millesimo M, Notarangelo LD, Musso T. Interleukin-15 (IL-15) induces IL-8 and monocyte chemotactic protein 1 production in human monocytes. Blood. 1997;90:2804–2809.[Abstract/Free Full Text]
  26. Alleva DG, Kaser SB, Monroy MA, Fenton MJ, Beller DI. IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition. J Immunol. 1997;159:2941–2951.[Abstract]
  27. McInnes IB, al-Mughales J, Field M, Leung BP, Huang FP, Dixon R, Sturrock RD, Wilkinson PC, Liew FY. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nat Med. 1996;2:175–182.[Medline] [Order article via Infotrieve]
  28. Wilkinson PC, Liew FY. Chemoattraction of human blood T lymphocytes by interleukin-15. J Exp Med. 1995;181:1255–1259.[Abstract/Free Full Text]
  29. Oppenheimer-Marks N, Brezinschek RI, Mohamadzadeh M, Vita R, Lipsky PE. Interleukin 15 is produced by endothelial cells and increases the transendothelial migration of T cells in vitro and in the SCID mouse-human rheumatoid arthritis model in vivo. J Clin Invest. 1998;101:1261–1272.[Medline] [Order article via Infotrieve]
  30. Tagaya Y, Bamford RN, DeFilippis AP, Waldmann TA. IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity. 1996;4:329–336.[Medline] [Order article via Infotrieve]
  31. McInnes IB, Liew FY. Interleukin 15: a proinflammatory role in rheumatoid arthritis synovitis. Immunol Today. 1998;19:75–79.[Medline] [Order article via Infotrieve]
  32. Washizu J, Nishimura H, Nakamura N, Nimura Y, Yoshikai Y. The NF-{kappa}B binding site is essential for transcriptional activation of the IL-15 gene. Immunogenetics. 1998;48:1–7.[Medline] [Order article via Infotrieve]
  33. McDonald PP, Russo MP, Ferrini S, Cassatella MA. Interleukin-15 (IL-15) induces NF-{kappa}B activation and IL-8 production in human neutrophils. Blood. 1998;92:4828–4835.[Abstract/Free Full Text]
  34. Sanders ME, Makgoba MW, Sharrow SO, Stephany D, Springer TA, Young HA, Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-{gamma} production. J Immunol. 1988;140:1401–1407.[Abstract]
  35. McHeyzer WM, Davis MM. Antigen-specific development of primary and memory T cells in vivo. Science. 1995;268:106–111.[Abstract/Free Full Text]
  36. 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;12:206–211.[Abstract/Free Full Text]
  37. Unutmaz D, Pileri P, Abrignani S. Antigen-independent activation of naive and memory resting T cells by a cytokine combination. J Exp Med. 1994;180:1159–1164.[Abstract/Free Full Text]
  38. Sugiura T, Kawaguchi Y, Harigai M, Takagi K, Ohta S, Fukasawa C, Hara M, Kamatani N. Increased CD40 expression on muscle cells of polymyositis and dermatomyositis: role of CD40-CD40 ligand interaction in IL-6, IL-8, IL-15, and monocyte chemoattractant protein-1 production. J Immunol. 2000;164:6593–6600.[Abstract/Free Full Text]
  39. Mach F, Schonbeck U, Sukhova GK, Bourcier T, Bonnefoy JY, Pober JS, Libby P. Functional CD40 ligand is expressed on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for CD40-CD40 ligand signaling in atherosclerosis. Proc Natl Acad Sci U S A. 1997;94:1931–1936.[Abstract/Free Full Text]
  40. Estess P, Nandi A, Mohamadzadeh M, Siegelman MH. Interleukin 15 induces endothelial hyaluronan expression in vitro and promotes activated T cell extravasation through a CD44-dependent pathway in vivo. J Exp Med. 1999;190:9–19.[Abstract/Free Full Text]
  41. DeGrendele HC, Estess P, Siegelman MH. Requirement for CD44 in activated T cell extravasation into an inflammatory site. Science. 1997;278:672–675.[Abstract/Free Full Text]
  42. Siegelman MH, Stanescu D, Estess P. The CD44-initiated pathway of T-cell extravasation uses VLA-4 but not LFA-1 for firm adhesion. J Clin Invest. 2000;105:683–691.[Medline] [Order article via Infotrieve]
  43. Brocke S, Piercy C, Steinman L, Weissman IL, Veromaa T. Antibodies to CD44 and integrin {alpha}4, but not L-selectin, prevent central nervous system inflammation and experimental encephalomyelitis by blocking secondary leukocyte recruitment. Proc Natl Acad Sci U S A. 1999;96:6896–6901.[Abstract/Free Full Text]




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