Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. 1995 Apr 25; 92(9): 3893–3897.

T lymphocytes from human atherosclerotic plaques recognize oxidized low density lipoprotein.


Atherosclerosis, an underlying cause of myocardial infarction, stroke, and other cardiovascular diseases, consists of focal plaques characterized by cholesterol deposition, fibrosis, and inflammation. The presence of activated T lymphocytes and macrophages and high expression of HLA class II molecules are indicative of a local immunologic activation in the atherosclerotic plaque, but the antigen(s) involved has not yet been identified. We established T-cell clones from human atherosclerotic plaques using polyclonal mitogens as stimuli and exposed the clones to potential antigens in the presence of autologous monocytes as antigen-presenting cells. Four of the 27 CD4+ clones responded to oxidized low density lipoprotein (oxLDL) by proliferation and cytokine secretion; this response was dependent on autologous antigen-presenting cells and restricted by HLA-DR. All clones that responded to oxLDL secreted interferon gamma upon activation, but only one produced interleukin 4, suggesting that the response to oxLDL results in immune activation and inflammation but may not be a strong stimulus to antibody production. No significant response to oxLDL could be detected in CD4+ T-cell clones derived from the peripheral blood of the same individuals. Together, the present data suggest that the inflammatory infiltrate in the atherosclerotic plaque is involved in a T-cell-dependent, autoimmune response to oxLDL.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.4M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. [PubMed]
  • Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. [PubMed]
  • Libby P, Hansson GK. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991 Jan;64(1):5–15. [PubMed]
  • Cybulsky MI, Gimbrone MA., Jr Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science. 1991 Feb 15;251(4995):788–791. [PubMed]
  • McMurray HF, Parthasarathy S, Steinberg D. Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes. J Clin Invest. 1993 Aug;92(2):1004–1008. [PMC free article] [PubMed]
  • Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–261. [PubMed]
  • Fogelman AM, Van Lenten BJ, Warden C, Haberland ME, Edwards PA. Macrophage lipoprotein receptors. J Cell Sci Suppl. 1988;9:135–149. [PubMed]
  • Ylä-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy S, Carew TE, Butler S, Witztum JL, Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989 Oct;84(4):1086–1095. [PMC free article] [PubMed]
  • Palinski W, Rosenfeld ME, Ylä-Herttuala S, Gurtner GC, Socher SS, Butler SW, Parthasarathy S, Carew TE, Steinberg D, Witztum JL. Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci U S A. 1989 Feb;86(4):1372–1376. [PMC free article] [PubMed]
  • Rosenfeld ME, Palinski W, Ylä-Herttuala S, Butler S, Witztum JL. Distribution of oxidation specific lipid-protein adducts and apolipoprotein B in atherosclerotic lesions of varying severity from WHHL rabbits. Arteriosclerosis. 1990 May-Jun;10(3):336–349. [PubMed]
  • Palinski W, Ylä-Herttuala S, Rosenfeld ME, Butler SW, Socher SA, Parthasarathy S, Curtiss LK, Witztum JL. Antisera and monoclonal antibodies specific for epitopes generated during oxidative modification of low density lipoprotein. Arteriosclerosis. 1990 May-Jun;10(3):325–335. [PubMed]
  • Salonen JT, Ylä-Herttuala S, Yamamoto R, Butler S, Korpela H, Salonen R, Nyyssönen K, Palinski W, Witztum JL. Autoantibody against oxidised LDL and progression of carotid atherosclerosis. Lancet. 1992 Apr 11;339(8798):883–887. [PubMed]
  • Ylä-Herttuala S, Palinski W, Butler SW, Picard S, Steinberg D, Witztum JL. Rabbit and human atherosclerotic lesions contain IgG that recognizes epitopes of oxidized LDL. Arterioscler Thromb. 1994 Jan;14(1):32–40. [PubMed]
  • 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 Feb;12(2):206–211. [PubMed]
  • Ehlers S, Smith KA. Differentiation of T cell lymphokine gene expression: the in vitro acquisition of T cell memory. J Exp Med. 1991 Jan 1;173(1):25–36. [PMC free article] [PubMed]
  • Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol. 1989 Jul;135(1):169–175. [PMC free article] [PubMed]
  • Jonasson L, Holm J, Skalli O, Gabbiani G, Hansson GK. Expression of class II transplantation antigen on vascular smooth muscle cells in human atherosclerosis. J Clin Invest. 1985 Jul;76(1):125–131. [PMC free article] [PubMed]
  • Hansson GK, Jonasson L, Holm J, Claesson-Welsh L. Class II MHC antigen expression in the atherosclerotic plaque: smooth muscle cells express HLA-DR, HLA-DQ and the invariant gamma chain. Clin Exp Immunol. 1986 May;64(2):261–268. [PMC free article] [PubMed]
  • Hansson GK. Immune and inflammatory mechanisms in the development of atherosclerosis. Br Heart J. 1993 Jan;69(1 Suppl):S38–S41. [PMC free article] [PubMed]
  • 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 Mar-Apr;6(2):131–138. [PubMed]
  • Emeson EE, Robertson AL., Jr T lymphocytes in aortic and coronary intimas. Their potential role in atherogenesis. Am J Pathol. 1988 Feb;130(2):369–376. [PMC free article] [PubMed]
  • van der Wal AC, Das PK, Bentz van de Berg D, van der Loos CM, Becker AE. Atherosclerotic lesions in humans. In situ immunophenotypic analysis suggesting an immune mediated response. Lab Invest. 1989 Aug;61(2):166–170. [PubMed]
  • Stemme S, Rymo L, Hansson GK. Polyclonal origin of T lymphocytes in human atherosclerotic plaques. Lab Invest. 1991 Dec;65(6):654–660. [PubMed]
  • HAVEL RJ, EDER HA, BRAGDON JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. [PMC free article] [PubMed]
  • Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D. Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A. 1984 Jun;81(12):3883–3887. [PMC free article] [PubMed]
  • Camejo G, Hurt-Camejo E, Rosengren B, Wiklund O, López F, Bondjers G. Modification of copper-catalyzed oxidation of low density lipoprotein by proteoglycans and glycosaminoglycans. J Lipid Res. 1991 Dec;32(12):1983–1991. [PubMed]
  • Kim RS, LaBella FS. Comparison of analytical methods for monitoring autoxidation profiles of authentic lipids. J Lipid Res. 1987 Sep;28(9):1110–1117. [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Lampson LA, Levy R. Two populations of Ia-like molecules on a human B cell line. J Immunol. 1980 Jul;125(1):293–299. [PubMed]
  • Sjögren-Jansson E, Jeansson S. Large-scale production of monoclonal antibodies in dialysis tubing. J Immunol Methods. 1985 Nov 28;84(1-2):359–364. [PubMed]
  • Williams AF, Galfrè G, Milstein C. Analysis of cell surfaces by xenogeneic myeloma-hybrid antibodies: differentiation antigens of rat lymphocytes. Cell. 1977 Nov;12(3):663–673. [PubMed]
  • Steinbrecher UP, Witztum JL, Parthasarathy S, Steinberg D. Decrease in reactive amino groups during oxidation or endothelial cell modification of LDL. Correlation with changes in receptor-mediated catabolism. Arteriosclerosis. 1987 Mar-Apr;7(2):135–143. [PubMed]
  • Hoff HF, O'Neil J, Chisolm GM, 3rd, Cole TB, Quehenberger O, Esterbauer H, Jürgens G. Modification of low density lipoprotein with 4-hydroxynonenal induces uptake by macrophages. Arteriosclerosis. 1989 Jul-Aug;9(4):538–549. [PubMed]
  • Steinbrecher UP. Oxidation of human low density lipoprotein results in derivatization of lysine residues of apolipoprotein B by lipid peroxide decomposition products. J Biol Chem. 1987 Mar 15;262(8):3603–3608. [PubMed]
  • Mackay CR, Marston WL, Dudler L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J Exp Med. 1990 Mar 1;171(3):801–817. [PMC free article] [PubMed]
  • Frostegård J, Wu R, Giscombe R, Holm G, Lefvert AK, Nilsson J. Induction of T-cell activation by oxidized low density lipoprotein. Arterioscler Thromb. 1992 Apr;12(4):461–467. [PubMed]
  • Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. [PubMed]
  • Barath P, Fishbein MC, Cao J, Berenson J, Helfant RH, Forrester JS. Detection and localization of tumor necrosis factor in human atheroma. Am J Cardiol. 1990 Feb 1;65(5):297–302. [PubMed]
  • Moyer CF, Sajuthi D, Tulli H, Williams JK. Synthesis of IL-1 alpha and IL-1 beta by arterial cells in atherosclerosis. Am J Pathol. 1991 Apr;138(4):951–960. [PMC free article] [PubMed]
  • Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb. 1994 Apr;14(4):605–616. [PubMed]
  • Griffith RL, Virella GT, Stevenson HC, Lopes-Virella MF. Low density lipoprotein metabolism by human macrophages activated with low density lipoprotein immune complexes. A possible mechanism of foam cell formation. J Exp Med. 1988 Sep 1;168(3):1041–1059. [PMC free article] [PubMed]
  • Adams DO. Molecular interactions in macrophage activation. Immunol Today. 1989 Feb;10(2):33–35. [PubMed]
  • Geng YJ, Hansson GK. Interferon-gamma inhibits scavenger receptor expression and foam cell formation in human monocyte-derived macrophages. J Clin Invest. 1992 Apr;89(4):1322–1330. [PMC free article] [PubMed]
  • Fong LG, Fong TA, Cooper AD. Inhibition of mouse macrophage degradation of acetyl-low density lipoprotein by interferon-gamma. J Biol Chem. 1990 Jul 15;265(20):11751–11760. [PubMed]
  • Hansson GK, Jonasson L, Holm J, Clowes MM, Clowes AW. Gamma-interferon regulates vascular smooth muscle proliferation and Ia antigen expression in vivo and in vitro. Circ Res. 1988 Oct;63(4):712–719. [PubMed]
  • Hansson GK, Hellstrand M, Rymo L, Rubbia L, Gabbiani G. Interferon gamma inhibits both proliferation and expression of differentiation-specific alpha-smooth muscle actin in arterial smooth muscle cells. J Exp Med. 1989 Nov 1;170(5):1595–1608. [PMC free article] [PubMed]
  • Amento EP, Ehsani N, Palmer H, Libby P. Cytokines and growth factors positively and negatively regulate interstitial collagen gene expression in human vascular smooth muscle cells. Arterioscler Thromb. 1991 Sep-Oct;11(5):1223–1230. [PubMed]
  • Geng Y, Hansson GK, Holme E. Interferon-gamma and tumor necrosis factor synergize to induce nitric oxide production and inhibit mitochondrial respiration in vascular smooth muscle cells. Circ Res. 1992 Nov;71(5):1268–1276. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences


Save items

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • Cited in Books
    Cited in Books
    NCBI Bookshelf books that cite the current articles.
  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles
  • Substance
    PubChem chemical substance records that cite the current articles. These references are taken from those provided on submitted PubChem chemical substance records.

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...