Published online before print September 27, 2007, doi: 10.1161/ATVBAHA.107.153064
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© 2007 American Heart Association, Inc.
Editorials |
The Influence of the Regulatory T Lymphocytes on Atherosclerosis
From the Heart Institute (I.G.), Hadassah University Hospital, Jerusalem, Israel; the Department of Medicine (R.G.), Massachusetts General Hospital, Boston; and the Vascular Research Division (A.H.L.), Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston.
Correspondence to Andrew H. Lichtman, MD, PhD, Department of Pathology, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB 752N, Boston, MA 02115. E-mail alichtman{at}rics.bwh.harvard.edu
Key Words: atherosclerosis • regulatory T cell • cytokines
Atherosclerosis is complex inflammatory disease of the arterial wall, in which T lymphocytes play a significant role.1 Since the recognition that T lymphocytes are present in human atherosclerotic plaque nearly 2 decades ago,2 research has focused on the functional importance of these cells in the atherosclerotic process. The majority of T lymphocytes in atherosclerotic lesions are CD4+ T-helper cells with a phenotype characteristic of the proinflammatory T-helper 1 (Th1) subset. These cells recognize specifically antigens that are produced in relative abundance in hypercholesterolemic individuals or in plaques including oxidatively modified LDL (Ox-LDL) and HSP60/65. The T cells are activated when macrophage or dendritic cells present these antigens to the T cells in plaques or lymphoid tissues. The Th1 cells produce inflammatory cytokines IFN-
, tumor necrosis factor (TNF)-
, and membrane CD40-ligand, which amplify the immune response through activation of macrophages, vascular smooth muscle cells, and endothelial cells.1
See page 2691
Many mechanisms have evolved to maintain immunologic self-tolerance and to limit responses to foreign antigens. One of these mechanisms involves regulatory T cells (Treg) that actively suppress responses of effector T cells. The best- characterized Treg are the natural CD4+CD25+ Treg that mature in the thymus and comprise 5% to 10% of peripheral CD4+ T cells.3 Other surface markers expressed by Treg include CTLA-4 and GITR. FoxP3, a forkhead family transcription factor, is a lineage specification factor for Treg and plays a crucial role in their suppressive function.4 Natural Treg are generated during thymic development, but Treg are also induced in peripheral tissues during immune responses. Treg express antigen receptors typical of effector T cells and are presumably activated by peptide antigens presented by APCs. They also require interleukin (IL)-2 for development and survival. Once activated, Treg may suppress other T cells of varying effector phenotype and antigen specificities, by contact-dependent mechanisms or through the secretion of antiinflammatory cytokines IL-10 and transforming growth factor (TGF)-β.
Given the importance of CD4+ effector T cells in atherosclerosis and the emerging data on Treg abnormalities in a variety of immunologically mediated diseases, the question of Treg influence on atherosclerosis has become a central theme of research in several laboratories. The presence of Treg in murine and human atherosclerotic lesions has now been firmly established.5–7 Experimental approaches that have been successfully used in other disease models to test the importance of Treg include the depletion of these cells by either genetic or antibody-mediated means, and the enrichment of Treg by adoptive transfer. In a seminal study by Ait-Oufella et al using all of these approaches, a direct effect of Treg on atherosclerosis was demonstrated in hypercholesterolemic mice.8 In particular, Treg deficiency (related to genetic ablation of the B71/2-CD28 costimulatory pathway in the hematopoietic compartment) was shown to enhance atherosclerotic lesion development in Ldlr–/– mice, and Treg depletion using an anti-CD25 antibody also enhanced atherosclerosis in ApoE–/– mice. Interestingly, Treg depletion did not influence lesion size or inflammatory phenotype when the host effector T cells were genetically engineered to be insensitive to TGF-β. This finding, together with previous work showing markedly enhanced atherosclerosis in ApoE–/– mice with TGF-β–resistant T cells,9 suggests that TGF-β is required for the atheroprotective effect of Treg. Furthermore, reduction in atherosclerosis in ApoE–/– mice has also been achieved through adoptive transfer of CD4+CD25+ regulatory T cells.8,10 Deficiency of the T cell costimulatory molecule ICOS results in enhanced atherosclerosis in Ldlr–/– mice, and this can be attributed to impaired Treg development and function.7
A central unresolved question about Treg biology is whether these cells behave in an antigen-specific or antigen-independent fashion. There seem to be 2 populations of potential Treg—those that originate from a committed lineage of FoxP3-expressing cells in the thymus11 and those that convert from mature CD4+ cells in the periphery (see Figure).12 It is not yet clear whether these peripherally converted cells acquire the full marker and regulatory characteristics of natural Treg, but they have been shown to be induced subsequent to a variety of manipulations such as exposure to TGF-β and IL-2 during activation, or by exposure to peptide antigen. It would be of great therapeutic interest if antigen-specific Treg populations could be induced to specifically suppress proatherogenic T cell responses, and thereby suppress atherosclerosis.
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Experimental evidence supporting the possibility of antigen-specific Treg in atherosclerosis does exist. Atherosclerotic disease in ApoE–/– can be attenuated by adoptive transfer of HSP60-specific Treg generated in vitro by stimulation of naïve T cells with HSP60 and immature dendritic cells.13 Furthermore, induced mucosal tolerance to HSP60 reduces atherosclerosis in mice.14,15 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Van Puijvelde et al also present data demonstrating that induction of oral tolerance to HSP60 and to small HSP60-peptide significantly reduces atherosclerotic plaque size in Ldlr–/– mice.16 This study goes beyond the previous studies with similar findings by showing the tolerogenic and atheroprotective effect is related to increased Treg activity. Oral tolerance toward HSP60 in the atherosclerotic mice was associated with increased Treg numbers in lymphoid tissues, and with increased ex vivo production of IL-10 and TGF-β by T cells from the mice. These findings are consistent with a Treg-dependent mechanism of suppression. In addition, mRNA encoding Treg markers (FoxP3, CTLA-4, CD25) were all increased in the atherosclerotic plaques of tolerized mice. Although the data presented by Van Puijvelde et al are highly suggestive that the atheroprotective effect of oral tolerance to HSP60 is attributable to Treg or Treg-associated cytokines, more definitive in vivo evidence is still needed, such as testing the effects of the oral tolerance regimen in ApoE–/– or Ldlr–/– mice deficient in Treg or relevant cytokines. Additionally, characterization of the Tregs induced by HSP60 in this model will shed light on the balance between thymically derived and peripherally converted Treg in human disease.
In a second paper in this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Treg are again shown to play a role in atherosclerotic disease, and interestingly both peripheral and thymic Treg may be involved. Taleb et al17 have explored the influence of leptin on atherosclerosis and have discovered a surprising effect of leptin signaling on Treg function. Leptin is a metabolic hormone produced by adipocytes that is increased in the serum of obese persons and may link obesity to increased atherogenic risk. Using a compound mutant mouse model of combined leptin and Ldlr deficiency, (Ldlr–/–xob/ob), the investigators show that leptin deficiency causes reduced atherosclerotic lesion development, independent of serum total cholesterol levels. This is associated with reduced Th1 responses, increased splenic expression of Foxp3, and increased in vitro Treg cell function. Taleb et al also show that Leptin receptor–deficient (db/db) mice have increased Treg numbers and suppressive function, providing further evidence that leptin signaling is important in Treg function. Importantly, in an in vivo study they demonstrate that Treg from db/db mice are more effective in reducing atherosclerosis and plaque inflammation than Treg from wild-type mice. Adoptive transfer of Treg-deficient lymphocytes and Treg cells from db/db mice into Apoe–/–/Rag2–/– recipients caused a greater reduction in lesion size and inhibited more interferon (INF)- production than transfer of Treg cells from wild-type mice. However, they make no distinction between the specific populations of Treg that are impaired by leptin signaling. The in vitro data that Treg from leptin-deficient mice have increased suppressive potential is in a non–antigen-specific system, and involves CD4+ CD25+ Treg that are thought to be thymically derived. Presumably peripheral antigen-specific Treg are also involved, especially given the impressive in vivo correlation between leptin deficiency and decreased atherosclerosis. This study does undoubtedly support the central role of functional Treg in the regulation of the immune response in atherosclerosis and provides intriguing data suggesting that leptin signaling negatively modulates Treg function. The findings provide a potentially important link between the inflammatory phenotype of the metabolic syndrome and Treg function.
Although the data reviewed here would suggest that Treg function has a central role in the regulation of proatherogenic T cell responses, there are numerous issues to be clarified. The mechanisms involved in Treg suppression of proatherogenic immune responses are still unresolved. Are they contact-dependent or are they cytokine-dependent as some studies would suggest7,8,16 or both? Does the regulation occur in lymphoid tissue, in the atherosclerotic lesion, or both? Finally, the opportunity to treat atherosclerosis by manipulating Treg responses will require a better characterization of the antigens that proatherogenic T cells recognize, and the antigens that drive development or peripheral induction of Treg that find their way into atherosclerotic lesions or relevant draining lymphoid tissues.
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Acknowledgments |
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Disclosures
None.
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Related Article:
- Defective Leptin/Leptin Receptor Signaling Improves Regulatory T Cell Immune Response and Protects Mice From Atherosclerosis
- Soraya Taleb, Olivier Herbin, Hafid Ait-Oufella, Wim Verreth, Pierre Gourdy, Véronique Barateau, Régine Merval, Bruno Esposito, Karine Clément, Paul Holvoet, Alain Tedgui, and Ziad Mallat
Arterioscler. Thromb. Vasc. Biol. 2007 27: 2691-2698.[Abstract] [Full Text] [PDF]
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