Review article
Regulatory T Cells and the Control of Modified Lipoprotein Autoimmunity-Driven Atherosclerosis

https://doi.org/10.1016/j.tcm.2010.02.010Get rights and content

It has long been recognized that arterial inflammation plays a key role in the development of atherosclerosis. More recent evidence has suggested that this inflammation is modulated by autoimmune responses against modified self-antigens, such as oxidized low-density lipoprotein, in the vascular wall. However, the role of the immune system in atherosclerosis appears to be more complex than in classic autoimmune diseases; and a number of protective immune responses have also been identified. One of the most important of these is carried out by the regulatory T cells. Regulatory T cells inhibit the development of autoimmunity by controlling the activity of autoreactive T cells. If the function of regulatory T cells is compromised in hypercholesterolemic mouse models of atherosclerosis, the development of disease becomes much more aggressive. In this review, we will discuss the possibility that the inflammatory activity in atherosclerotic lesions depends on the balance between plaque antigen-specific proinflammatory Th1-type T cells and anti-inflammatory regulatory T cells specific for the same antigen. We will also discuss the role of hypercholesterolemia in generation of these modified self-antigens as well as ongoing research aiming to develop novel immune-modulating therapy for prevention of cardiovascular disease by targeting these processes.

Section snippets

Autoimmunity Against Antigens Induced by Hypercholesterolemia Promotes Atherosclerosis

The first evidence for involvement of autoimmune responses in atherosclerosis was discovered more than 20 years ago when Jonasson et al. (1985) demonstrated expression of MHC class II antigen as well as the presence of activated T cells in human atherosclerotic plaques. Findings from initial studies with the use of hypercholesterolemic mice deficient in all lymphocytes (resulting from Rag or SCID gene mutations) were not entirely conclusive and suggested a role for immunity primarily in animals

Oxidized LDL is a Major Autoantigen in Atherosclerosis

The circumstance that the experimental studies describing the pathogenic role of Th1 immunity in atherosclerosis were based on induction of disease by hypercholesterolemia suggests that the relevant autoantigen is a lipoprotein or possibly a protein modified by lipids. Most attention has focused on the role of oxidized LDL in these processes. Antibodies against oxidized LDL are common in humans (Hulthe 2004). Oxidized LDL, as well as oxidized LDL autoantibodies, has also been isolated from

Immune-Modulation as a Novel Therapeutic Approach for Prevention of Atherosclerosis

The finding that atheroprotective immune responses could be activated by immunization with oxidized LDL pointed to the fascinating possibility of developing an atherosclerosis vaccine. Several laboratories initiated studies to reveal the active antigens in oxidized LDL and to characterize mechanisms involved in the protective effect. The result of these studies demonstrated the presence of multiple antigens related either to peptide fragments of B-100 (Fredrikson et al. 2003a) or to oxidized

Tregs Control Autoimmunity

The most important function of the immune system is to recognize and eliminate infectious microorganisms. In doing so, it is vital that the immune system can differentiate these pathogens from self-antigens. However, a complete deletion of all autoreactive T cells would impair the effectiveness of the infectious defense because some self-antigens share structural similarities with foreign pathogens. As a result, a fraction of moderately self-reactive T cells escapes deletion in the thymus; and

Tregs and Atherosclerosis

Several lines of evidence have implicated dysregulation of Treg function in atherosclerosis (Mallat et al. 2007). Atherosclerotic plaques contains relatively few FoxP3-positive Tregs (1%–5% of all T cells) as compared with normal arterial tissue or inflammatory skin lesions, where Tregs constitute about 25% of all T cells, suggesting that local tolerance protection is impaired in atherosclerotic plaques (de Boer et al. 2007). Regulatory T cell numbers are lower in old, atherosclerotic ApoE−/−

Therapeutic Targeting of Tregs

The identification of Tregs as an important protective factor in atherosclerosis has focused the attention on these cells as possible targets for intervention. As discussed above, there is accumulating evidence that the rate of progression of the disease is determined by the balance between proinflammatory Th1 and anti-inflammatory Treg responses against modified vascular antigens. The possibility to modulate this balance toward a predominance of Tregs represents an attractive therapeutic

Future Perspectives

The emerging recognition of the role of plaque antigen autoimmunity in atherosclerosis has focused attention on the possibility of developing immune-modulating therapy for prevention of cardiovascular disease. A first generation of such therapies is now approaching clinical testing, and phase I safety studies of an apo-B-peptide-based atherosclerosis vaccine are expected to be initiated during 2010. However, the relatively incomplete understanding of the mode of action of these novel therapies,

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