Mechanism of Disease: Evolving Role of Regulatory T Cell in Atherosclerosis

Table 1.

A Comparison of Natural and Adaptive Regulatory T Cells

Box 1.

Evidence of Operative Autoimmune-like Responses in Experimental and Human Atherosclerosis

Hansson GK (2005) Inflammation, atherosclerosis, and coronary artery disease.N Engl J Med 352: 1685-1695
Hansson GK and Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6: 508-519
Shah PK et al. (2004) Vaccination for atherosclerosis: a novel therapeutic paradigm. Expert Rev Vaccines 3: 711-716
Abbas AK et al. (1996) Functional diversity of helper T lymphocytes. Nature 383: 787-793
Park H et al. (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.Nat Immunol 6: 1133-1141
McGeachy MJ and Cua DJ (2008) Th17 cell differentiation: the long and winding road. Immunity 4: 445-453
Bluestone JA and Abbas AK (2003) Natural versus adaptive regulatory T cells. Nat Rev Immunol 3: 253-257
Sakaguchi S et al. (2006) Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212: 8-27
Sakaguchi S et al. (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor á-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155: 1151-1164
Battaglia M et al. (2006) Tr1 cells: from discovery to their clinical application. Semin Immunol 18: 120-127
Walker MR et al. (2005) De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells. Proc Natl Acad Sci USA 102: 4103-4108
Vukmanovic-Stejic M et al. (2006) Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest 116: 2423-2433
Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6: 345-352
Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22: 531-562
Huehn J et al. (2004) Developmental stage, phenotype, and migration distinguish naive- and effector/memorylike CD4+ regulatory T cells. J Exp Med 199: 303-313
Yurchenko E et al. (2006) CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence. J Exp Med 203: 2451-2460
Huang CT et al. (2004) Role of LAG-3 in regulatory T cells. Immunity 21: 503-513
Ronchetti S et al. (2004) GITR, a member of the TNF receptor superfamily, is costimulatory to mouse T lymphocyte subpopulations. Eur J Immunol 34: 613-622
Fontenot JD et al. (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330-336
Hori S et al. (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057-1061
Khattri R et al. (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4: 337-342
Brunkow ME et al. (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27: 68-73
Bennett CL et al. (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27: 20-21
Allan SE et al. (2005) The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 115: 3276-3284
Shevach EM (2006) From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 25: 195-201
Miyara M and Sakaguchi S (2007) Natural regulatory T cells: mechanisms of suppression. Trends Mol Med 13: 108-116
Lohr J et al. (2006) Regulatory T cells in the periphery. Immunol Rev 212: 149-162
Chen W (2003) TGF-beta: the missing link in CD4+CD25+ regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev 14: 85-89
Thornton AM and Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188: 287-296
Torgerson TR (2006) Regulatory T cells in human autoimmune diseases. Springer Semin Immunopathol 28: 63-76
Viglietta V et al. (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199: 971-979
Baecher-Allan C and Hafler DA (2006) Human regulatory T cells and their role in autoimmune disease. Immunol Rev 212: 203-216
Zou W (2006) Regulatory T cells, tumour Immunity and immunotherapy. Nat Rev Immunol 6: 295-307
Curiel TJ et al. (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10: 942-949
Binder C et al. (2002) Innate and acquired Immunity in atherogenesis. Nat Med 8: 1218-1226
Verma S et al. (2005) C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med 21: 29-36
Wick G et al. (2004) Autoimmune and inflammatory mechanisms in atherosclerosis. Annu Rev Immunol 22: 361-403
Xu Q et al. (1993) Staining of endothelial cells and macrophages in atherosclerotic lesions with human heat-shock protein-reactive antisera. Arterioscler Thromb 13: 1763-1769
Palinski W et al. (1989) Low density lipoprotein undergoes oxidative modification in vivo. Proc Natl Acad Sci USA 86: 1372-1376
George J et al. (1999) Immunolocalization of beta2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression. Circulation 99: 2227-2230
Palinski W et al. (1995) Immunization of low density lipoprotein (LDL) receptor-deficient rabbits with homologous malondialdehyde-modified LDL reduces atherogenesis. Proc Natl Acad Sci USA 92: 821-825
Xu Q et al. (1992) Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat shock protein 65. Arterioscler Thromb 12: 789-799
George J et al. (1998) Induction of early atherosclerosis in LDL-receptor-deficient mice immunized with beta2-glycoprotein I. Circulation 98: 1108-1115
George J et al. (2000) Adoptive transfer of beta(2)-glycoprotein I-reactive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice. Circulation 102: 1822-1827
Zhou X et al. (2000) Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice. Circulation 102: 2919-2922
George J et al. (2001) 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 P Cardiol 38: 900-905
Harats D et al. (2002) Oral tolerance with heat shock protein 65 attenuates Mycobacterium tuberculosisinduced and high-fat-diet-driven atherosclerotic lesions. J Am Coll P Cardiol 40: 1333-1338
Maron R et al. (2002) Mucosal administration of heat shock protein-65 decreases atherosclerosis and inflammation in aortic arch of low-density lipoprotein receptor-deficient mice. Circulation 106: 1708-1715
van Puijvelde GH et al. (2006) Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis. Circulation 114: 1968-1976
Stoll G and Bendszus M (2006) Inflammation and atherosclerosis: novel insights into plaque formation and destabilization. Stroke 37: 1923-1932
Mallat Z et al. (2003) Induction of a regulatory T cell type 1 response reduces the development of atherosclerosis in apolipoprotein E-knockout mice. Circulation 108: 1232-1237
Faria AM and Weiner HL (2005) Oral tolerance. Immunol Rev 206: 232-259
George J et al. (2004) Suppression of early atherosclerosis in LDL-receptor deficient mice by oral tolerance with beta 2-glycoprotein I. Cardiovasc Res 62: 603-609
George J et al. (1998) Hyperimmunization of apo-Edeficient mice with homologous malondialdehyde lowdensity lipoprotein suppresses early atherogenesis. Atherosclerosis 138: 147-152
van Puijvelde GH et al. (2007) Induction of oral tolerance to HSP60 or an HSP60-peptide activates T cell regulation and reduces atherosclerosis. Arterioscler Thromb Vasc Biol 27: 2677-2683
Tedgui A and Mallat Z (2006) Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 86: 515-581
Mallat Z et al. (1999) Protective role of interleukin-10 in atherosclerosis. Circ Res 85: e17-e24
Robertson AK et al. (2003) Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J Clin Invest 112: 1342-1350
Ait-Oufella H et al. (2006) Natural regulatory T cells control the development of atherosclerosis in mice. Nat Med 12: 178-180
Gotsman I et al. (2006) Impaired regulatory T-cell response and enhanced atherosclerosis in the absence of inducible costimulatory molecule. Circulation 114: 2047-2055
Mor A et al. (2007) Role of naturally occurring CD4+ CD25+ regulatory T cells in experimental atherosclerosis. Arterioscler Thromb Vasc Biol 27: 893-900
Schwartz SM et al. (2007) Plaque rupture in humans and mice. Arterioscler Thromb Vasc Biol 27: 705-713
Liuzzo G et al. (1999) Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 100: 2135-2139
Liuzzo G et al. (2001) Molecular fingerprint of interferon-gamma signaling in unstable angina. Circulation 103: 1509-1514
Grainger DJ et al. (1995) The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat Med 1: 74-79
Smith DA et al. (2001) Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina. Circulation 104: 746-749
Mor A et al. (2006) Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J 27: 2530-2537
Han SF et al. (2007) The opposite-direction modulation of CD4+CD25+ Tregs and T helper 1 cells in acute coronary syndromes. Clin Immunol 124: 90-97
de Boer OJ et al. (2007) Low numbers of FOXP3 positive regulatory T cells are present in all developmental stages of human atherosclerotic lesions. PLoS ONE 2: e779
Greenwood J et al. (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6: 358-370
Mausner-Fainberg K et al. (2008) The effect of HMG-CoA reductase inhibitors on naturally occurring CD4(+)CD25(+) T cells. Atherosclerosis 197: 829-839
Zhou X and Hansson GK (2004) Immunomodulation and vaccination for atherosclerosis. Expert Opin Biol Ther 4: 599-612
Schiopu A et al. (2007) Recombinant antibodies to an oxidized low-density lipoprotein epitope induce rapid regression of atherosclerosis in apobec-1(-/-)/ low-density lipoprotein receptor(-/-) mice. J Am Coll P Cardiol 50: 2313-2318

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Summary and Introduction

Summary

Atherosclerosis and related complications still represent the major cause of morbidity and mortality in the western world. The mechanisms that govern the progression and destabilization of atheromatous lesions are multiple and complex. Despite their widespread use, lipid-lowering agents do not provide sufficient protection from future clinical cardiovascular-associated events. Interest in the role of immunity in atherosclerosis and support for this relationship has grown significantly over recent years. This paradigm, in which inflammation is an instrumental process in plaque development and rupture, is further supported by studies showing that immune subsets are operative in atherosclerosis. Regulatory T-cell subpopulations consist of lymphocytes—with several phenotypic markers—that share the ability to suppress, by various mechanisms, inflammatory responses. These regulatory T cells consist of subsets such as interleukin-10 secreting type I regulatory cells, type 3 effector T-helper cells that produce transforming growth factor-β, as well as adaptive and natural CD4⁺CD25⁺ regulatory T cells. In this Review, I focus on the direct and indirect evidence for the involvement of regulatory T cells in atherogenesis in experimental models and in humans. The growing knowledge of the role of regulatory T cells could result in the future development of novel therapeutic modalities to attenuate atherosclerosis and stabilize vulnerable plaques.

Introduction

The immune system has an influential role in the pathogenesis of atherosclerosis.^[1,2] Elucidation of this relationship has focused research on the potential discovery of markers with diagnostic and prognostic value. In this context, an intriguing possibility is the use of knowledge already gathered on the immune mechanisms governing plaque growth and destabilization to develop novel therapeutic strategies based on manipulation of the immune system.^[3] Here I review T cells with regulatory properties and the basic milestones that led to an understanding of the importance of this T-cell subset in atherogenesis, and the potential roles this cell population could have in atherosclerosis.

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Lineage Specification of CD4+ T Cells

References

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Table 1.

Box 1.

Mechanisms of Disease: The Evolving Role of Regulatory T Cells in Atherosclerosis

Summary and Introduction

Summary

Introduction

Table of Contents

Table 1.

Box 1.

References

Faculty and Disclosures

Author(s)

Jacob George, MD

Editor(s)

Hannah Camm

Mechanisms of Disease: The Evolving Role of Regulatory T Cells in Atherosclerosis

Summary and Introduction

Summary

Introduction

Table of Contents