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Cardiovascular Research 2003 60(1):78-86; doi:10.1016/S0008-6363(03)00341-9
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Copyright © 2003, European Society of Cardiology

T lymphocytes in atherogenesis—functional aspects and antigenic repertoire

Onno J de Boer*, Anton E Becker and Allard C van der Wal

Department of Cardiovascular Pathology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

*Corresponding author. Tel.: +31-20-566-4369; fax: +31-20-691-4738. Email address: o.j.deboer{at}amc.uva.nl

Received 13 December 2002; accepted 25 February 2003

KEYWORDS Atherosclerosis; Immunology; Infection/inflammation; T-cells; Cytokines


   1. Introduction
Top
 1. Introduction
2. T-cell immune responses...
 3. T-cells and initiators...
 4. Conclusions
 References
 
Atherosclerosis represents an inflammatory and reparative response to chronic or episodic injury of arterial intima [1]. During the longstanding process of plaque formation a myriad of secretory products of inflammatory cells is released in the plaque, likely connected to the nature and extent of injury to the vessel wall. These inflammatory mediators do not only have profound effects on growth and morphologic differentiation of plaques, but eventually may also initiate plaque rupture, and thus life threatening complications such as myocardial infarction and stroke [2]. Such insights have led to intense investigations over the past years tempting to unravel molecular and cellular basis of plaque inflammation, which include also factors that initiate or sustain the inflammatory response. Cell types that take part in plaque inflammation are macrophages, T-lymphocytes, mast cells and dendritic cells. Among these, the participation of T cells in atherogenesis is relevant for several reasons. First, T-cells are immune regulatory cells, which, once activated, are able to secrete cytokines or express surface molecules with bioactive potential. These receptors and cytokines are capable of modulating the type and intensity of the inflammatory response, and also influence the microenvironment (growth behavior of vascular smooth muscle cells, synthesis and degradation of extracellular matrix proteins), implying that they may affect the stability of the plaque. Second, T-lymphocytes are cells with an immunological memory; they are genetically programmed to respond only to a very specific sequence of peptides (antigens), which is unique for each T-cell. Such antigenic recognition leads to activation, clonal expansion and/or cytokine production; in other words, initiating a cell mediated inflammatory response. Knowing the antigen specificity of T cells in plaques could thus provide information about the causes of plaque inflammation, and such information can be considered pivotal to develop treatment modalities that interfere with the process of plaque inflammation [3]. In this review we will focus on these aspects of T-cell immunology in atherosclerotic plaques.


   2. T-cell immune responses in atherosclerotic lesions
Top
 1. Introduction
 2. T-cell immune responses...
3. T-cells and initiators...
 4. Conclusions
 References
 
2.1. Basic aspects of T-cell immunity
In the atherosclerotic plaque both innate- and adaptive immune responses play a role. Innate immunity represents a phylogenetically old, fast and strong but not very specific first line of defense, involving receptors that recognize evolutionary conserved patterns on antigens such as scavenger receptors on macrophages [4] or TOLL-like receptors (reviewed elsewhere in this issue). Scavenger receptor related phagocytosis of (oxidized) lipids with consequent release of inflammatory proteins such as matrix metalloproteinases is a well-known example [5]. Adaptive immunity on the other hand, which is the scope of this review, involves clonal selection and expansion of lymphocyte subsets, which are either T-cells or B-cells, in response to antigen recognition, and is therefore considered highly specific. B-cells respond to single antigens by the production of specific immunoglobulins. However, inside atherosclerotic plaques the numbers of plasma cells and B-cells are very low, making it very unlikely that these cells play a role in intimal inflammation [6–8]. B cells do however play a role in atherosclerosis, and several studies have suggested that B cells are in fact atheroprotective [9,10]. T cells on the other hand, are numerous in plaques [6–8,11]. T cells act either through a direct cytotoxic attack (mainly CD8+ T cells), or by helping other immune cells through the production of cytokines or cell–cell interactions via surface receptors [4]. Every T cell only recognizes one antigen (polypeptide), in relation with an MHC molecule, expressed by antigen-presenting cells. CD4+ helper T cells recognize antigens in the context of an MHC class II molecule (HLA-DR, -DP or -DQ). MHC class II molecules present (exogenous) antigens that have been phagocytosed and processed by antigen-presenting cells. CD8+ T-cells (T suppressor/cytotoxic cells) on the other hand recognize antigens in the context of MHC class I molecules. MHC class I molecules contain peptides from proteins synthesized by the cell, including viral encoded proteins [12]. Early after antigenic stimulation, activation receptors like CD25, CD40L and CD69 are expressed on the cell surface and several cytokines and chemokines are secreted in a pattern, which is specific for the type of T-cell involved. CD4+ Th1 cells produce large amounts of interferon-gamma (IFN-{gamma}, interleukin-2 (IL-2), TNF-{alpha} and lymphotoxin, and these cells are particularly important directing cell mediated immune responses leading to the eradication of intracellular pathogens. CD4+ Th2 cells on the other hand, are characterized by the secretion of IL-4, IL-5 and IL-10 which promotes humoral immune responses [13]. Th0 cells are cells that do not exhibit such a distinct cytokine secretion profile and produce both IFN and IL4 [13]. Recently another subpopulation of T cells were described, designated Th3, which are characterized by their production of anti inflammatory cytokine TGF-β [14]. Another subset of T cells, T regulatory 1 (Tr1) cells, are cells that are characterized by the secretion of high levels of IL-10 [15], but at present, there are no studies that analyzed the presence of these T cell subsets in plaques.

2.2. Lymphocytes in various stages of plaque developments
The process of lesion formation starts early in life at lesion prone areas such as flow dividers and branching points, and particularly under atherogenic conditions such as hypercholesterolemia [1]. Oxidized lipoproteins activate monocytes/macrophages and endothelial cells, which leads to the expression of adhesion molecules on the endothelial cells and local production of chemokines. In immunocompetent mice and in humans, the recruitment of inflammatory cells, including T-cells, into the arterial intima is a constant feature throughout all stages of development and growth of lesions. T-cells can be observed immunohistochemically in pre-lesional stages and in early lesions such as fatty streaks including CD25+ forms, indicating that they are functionally active [7]. In fact, the fatty streak is a lesion entirely composed of mononuclear inflammatory cells [1]. Immunodeficient apoE–/– mice (atherogenic mice lacking functional B and/or T lymphocytes) do develop atherosclerotic plaques, although these lesions tend to be smaller in size [16,17] (see Table 1)


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  		Table 1 Murine experimental models to study the effect of T-cells and T cell derived cytokines on atherosclerosis

 
Immunohistochemical studies have shown that both CD4 and CD8 positive T-cells are present in human atherosclerotic lesions almost through all stages of plaque development, although in later stages of plaque development CD4 cells nearly always dominate [6,7]. T-cells expressing the gamma delta T cell receptor and NK cells are rare in plaques. The number of T-cells present in human plaques is highly variable and also relates to the overall plaque morphology. In fibrous plaques, which are characterized by fibrocellular and fibrosclerotic tissue, the number of T-cells are low whereas lesions with large lipid pools contain on average large numbers of T cells [18].

Regarding the antigen specificity of plaque T cells, it has been considered of importance to know whether responses inside lesions are oligo- or polyclonal. Analysis of the T cell repertoire of (early) murine plaques, by means of assessment of T-cell receptor rearrangement patterns, have shown that the T cell population in plaques are from oligoclonal origin, suggesting local, antigen driven T cell expansion [19]. However, analysis of the T cell population in human plaques revealed a polyclonal population [20]. This does not necessarily imply that clonal expansion in human plaques does not occur. First, human plaques are ‘old’ compared to the situation in mice, and the T cell population present in these lesions is the result of many years of migration and selection. Furthermore, it is most likely that several antigens are involved in atherogenesis, which also would lead to the presence of many different clones.

Several recent reports have shown that the Th1 subset of T-cells is most important during atherogenesis. Analysis of mRNA derived from plaque tissue shows that Th1 cytokines are the most prevalent in human plaques [21,22]. Also functional analysis of plaque derived T-cells clones shows that IFN-{gamma} is the dominant cytokine produced by intraplaque T-cells [23]. Several in vivo animal studies have also stressed the importance of Th1 immunity in atherogenesis (see Table 1). For example, ApoE–/– mice with a dysfunctional IFN-{gamma} receptor develop lesions that are smaller compared to controls. Moreover, such mice develop lesions with a much higher collagen content, i.e. have a more stable tissue composition [24]. Similarly, exogenous administered IFN-{gamma} to apoE –/– mice promotes lesions development [25]. Likewise, lesion development in atherosclerosis prone mice can be inhibited by pharmacological blocking of the Th1 response [26], or by stimulating the Th2 response (which counteracts Th1 activity), by the overproduction of IL-10 [27].

2.3. Site of T-cell recruitment
The arterial endothelium covering the intimal surface has been considered as the principal site of leukocyte entrance in early lesions, but in older, mature plaques an alternative site should also be taken into account. In these advanced plaques, and particularly those with high lipid content, newly formed capillary vessels (angiogenesis) can be frequently observed. They are derived from the underlying arterial vasa vasorum, penetrate the often-attenuated media, and occupy the base of the lipid core and the shoulder parts of plaques. These latter areas are of special interest, because these are the sites where plaques are most vulnerable, and most ruptures take place. Immunohistochemical studies have revealed clusters of inflammatory cells, including activated T-cells in proximity of these microvessels lined with activated (E-selectin and VCAM positive) endothelium, suggesting that at these sites indeed a local inflammatory burst is initiated [18,28,29].

2.4. T-cells and clinical manifestations of atherosclerosis
The importance of the process of T-cell activation in advanced atherosclerotic plaques stems mainly from clinico–pathologic observations, on lesions derived from patients with symptomatic coronary artery disease. Active inflammation, in which HLA DR+ T-cells participate, is an almost constant finding at rupture sites of thrombosed coronary plaques of patients who died of acute myocardial infarction (see Fig. 1) [30]. We also investigated the frequency of activated T-cells in plaque tissues obtained from patients with stable angina and of patients with acute coronary disease (unstable angina or acute myocardial infarction) using directional coronary atherectomy specimens (see Fig. 2). In the plaque tissues of patients with stable coronary artery disease only a small percentage of the T-cells appeared to be activated. On the other hand, in the culprit lesions from patients with unstable coronary syndromes, and particularly those with myocardial infarction, the frequency of activated T-cells, assessed by expression of several activation markers was increased significantly [31,32]. Such findings suggest that around the time of onset of acute syndromes (which may be days to weeks) substantial T-cell activation takes place, with as a consequence, tissue-remodeling activity.


Figure 1
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  		Fig. 1 Immunohistochemical double staining of an atherosclerotic plaque with HLA-DR (blue) and pan T cell marker CD3 (red). T-cells are in close proximity of (HLA-DR positive) macrophages. In addition, several T-cells are also HLA-DR positive (double stained cells, purple).

 

Figure 2
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  		Fig. 2 Immunohistochemical double staining with pan T cell marker CD3 (in blue) and T cell activation marker CD40L (red). Note the expression of CD40L on several T-cells in this lesion (double stained cells are indicated by arrows).

 
Not only T-cells inside the plaque, but also circulating T-cells in the peripheral blood appears to change around the time of clinically manifest atherosclerotic disease. Again, most data are retrieved from patients with coronary heart disease. Several studies have shown an increase in activated peripheral T-cells [33], or serum levels of soluble T cell activation markers in patients with coronary artery disease, like CD25 [34,35] or CD40L [36,37]. Systemic markers for lymphocyte activation, however, may not necessarily relate to the situation in the atherosclerotic plaque, and may arise from another inflammatory (infectious) disease.

Liuzzo et al. reported increased numbers CD4+CD28 negative T-cells (‘CD28 null cells’) in the peripheral blood of patient with unstable angina [38]. In vitro analysis of these cells has shown that these cells synthesize increased levels of IFN-{gamma}, and possibly result from persistent antigenic stimulation [38]. Still, it is not clear what the functional relevance of these (peripheral) T-cells is for individual plaques. It is interesting to note however that immunohistochemical analysis of plaque tissue has shown that the vast majority of intraplaque T-cells are also CD28 negative.


   3. T-cells and initiators of plaque inflammation
Top
 1. Introduction
 2. T-cell immune responses...
 3. T-cells and initiators...
4. Conclusions
 References
 
Considering the role of T-cells in regulation of the plaque inflammatory responses, it is obvious that factors that trigger T-cell activation need to be identified. Several pathways are currently under investigation.

3.1. Antigen independent T-cell activation
One pathway of T-cell activation that is independent of antigen presentation can be mediated by the cytokine IL15. IL15 is an interesting cytokine since it exerts multiple effects on T-cell function, including proliferation induction, generation of cytotoxic cells, stimulation of cytokine production, and induction of the activation antigens CD40L and CD69, inhibition of T-cell apoptosis, all independent of direct presentation and recognition of antigens [39–41]. We recently reported that the majority of plaque macrophages express high levels of IL15 mRNA and it's protein [42]. In the studied plaques we found activated T-cells in close apposition with IL15 positive macrophages, and in vitro T-cell lines derived from plaques were highly responsive to IL15, suggesting that such a pathway of T-cell activation indeed could occur in plaques. Most abundant IL15 was found in lipid rich plaques and in lipid laden foam cells which could implicate that lipid metabolism in the plaque triggers local T-cell activation and survival. One could speculate that particularly ox-LDL is involved in the upregulation of IL-15, since this product also increases the secretion of cytokines such as IL-2, IL-8 and MCP-1. The relative contribution of this pathway to plaque T cell activation needs to be established, although it is tempting to speculate that such processes may explain why the effects of plaque inflammation are most prominent in lesions with high lipid contents [2,43].

3.2. Antigen specific T-cell activation
Several antigenic structures have been forwarded to play a role in the antigenic stimulation of plaque inflammation, which include lipid constituents, altered matrix components, advanced glycosylation end products, heat shock proteins and components of micro-organisms. The first publication of T-cells specific for plaque antigens concerned oxidized LDL, an ‘autoantigen’. Stemme et al. reported that T cell clones derived from human plaques respond to ox-LDL epitopes [44]. Although this finding is of great interest since it provided another link between lipid and inflammation, the actual number of obtained clones (4 from three different patients) is too small to estimate a frequency distribution.

Another autoantigen of interest is platelet β2-glycoprotein1b. George et al. showed that transfer of β2 glycoprotein-1 reactive T-cells gave rise to enhanced plaque formation in LDLR–/– mice [45]. Antibodies against β2 glycoprotein-1 can be detected in serum of patients with Lupus Erythematosus and, although speculative, immune responses against this platelet protein could contribute to accelerated forms of atherosclerosis which occur in Lupus patients [46,47].

There is growing evidence that infectious micro-organisms may play a pathogenic role in coronary artery disease. Such evidence stems from serological associations between the risk of atherosclerotic cardiovascular disease and raised serum antibody titres against several microorganisms including C. pneumoniae [48], H. pylori [49], periodontal pathogens [50], CMV [51], hepatitis A virus [52], enteroviruses [53], and EBV [54]. Furthermore, such infections appear to exert an accumulating effect on the future risk of myocardial infarction and stroke: sero-epidemiological associations of single infectious pathogens are usually weak or even controversial, but when the total pathogen of a patient increases (in some patients more then 5) the relative risk of future cardiovascular death may increase up to 5.1 [55]. These authors concluded that the number of infectious pathogens to which an individual has been exposed independently contributes to the long-term prognosis in patients with documented CAD. Also other studies have revealed a similar impact of pathogen burden on cardiovascular risk [56].

At present, it is not clear how these pathogens contribute to the pathogenesis of atherosclerosis, but several mechanisms may be involved. First, infectious pathogens could affect plaque growth and/or plaque thrombosis through circulating cytokines (interleukin-6) and acute phase proteins (C-reactive protein, fibrinogen). Second, several of these microorganisms have been detected in situ in plaque tissue, and thus could potentially stimulate plaque inflammation [57,58]

The most extensively studied microorganism at present is C. pneumoniae (Cp). It can be detected in plaque tissue with various techniques (PCR, immunohistochemistry and electron-microscopy), and has also been cultured from human plaques [59–61]. Studies in hypercholesterolemic animals moreover, have shown that Cp superimposed on hypercholesterolemia accelerates lesion formation, and increased T-cell infiltration and lesion maturation in plaques has been noticed in plaques when infected animals (APO E Leiden mice) were compared with non infected controls [62,63]. Obviously such information cannot be obtained from human plaques with presently available techniques, but testing antigenic specificity of the human plaque T-cell population may provide important clues. We isolated T-cells from fresh atherosclerotic plaque obtained by carotid endarterectomy from symptomatic patients. From each plaque T cell lines were generated, and the antigenic specificity of these lines for Cp was analysed by culturing these cells in the presence of autologous antigen presenting cells and Cp elementary bodies. We found significant responses (positive proliferation indices) in five out of eight patients, indicating that these lines contained T-cells specific for Cp. Cloning of three of the Cp positive T cell lines further revealed that Cp specific T-cells were CD4 positive and most of them showed a Th1 cytokine secretion profile [64]. Also other investigators showed that Cp specific T-cells are present carotid plaques, and in abdominal atherosclerotic aneurysms always in a subpopulation of patients [65–67]. These findings indicate that indeed in a subpopulation of patients with atherosclerotic vascular disease Cp antigens must at least be capable of triggering or sustaining an inflammatory response inside the plaque.

For a long time also periodontitis and caries have been associated with increased risk of cardiovascular disease [68] Recently, DNA of several pathogens responsible for periodontal pathology, P. gingivalis, P. intermedia, A. actinomycetem-comitans and B. forsythus has been identified in human atherosclerotic plaques [69]. Choi et al. generated T cell lines from human atherosclerotic plaques and found that T-cells responsive with one of these pathogens, P. gingivalis, could be generated from atherosclerotic plaques from patients with a history of periodontal disease only, and not from patients without such a history [70]. These results suggest that P. gingivalis could also contribute to T cell mediated plaque inflammation in a specific group of patients.

Another common pathogen potentially capable of eliciting local, intraplaque T cell responses is Epstein Barr Virus (EBV). EBV is a very common pathogen, and more then 90% of individuals worldwide are infected. Infection with EBV is associated with atherosclerotic disease [54], and, moreover, is an independent risk factor for future cardiovascular death [55]. Furthermore, EBV has been detected in the majority atherosclerotic plaques by means of PCR analyis [71]. We analyzed the proliferative responses of plaque derived T lymphocytes with autologous EBV transformed B lymphocytes, and found that more than half of these T cell lines indeed respond with EBV (see also Fig. 3). In addition, we frequently observed the combined presence of EBV virus (determined by PCR) and EBV specific T-cells in the same lesions, suggesting that also EBV is a common pathogen, capable of triggering a local, intraplaque T cell mediated immune response [72].


Figure 3
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  		Fig. 3 Proliferative responses of 16 T cell lines, generated from plaques of human carotid arteries, illustrating their specificity for C. pneumoniae and Epstein Barr Virus. Note that five out of eight plaque derived T cell lines responded to EBV (stimulation index>3), and four out of eight T cell lines respond with C. pneumoniae.

 
Heat shock proteins (Hsp) or stress proteins are induced by cells in response to factors threatening the integrity of the cells, such as high temperature, mechanical stress and infection. Hsp are highly conserved between prokaryotic and eukaryotic cells, and therefore it has been suggested that hsp could represent a link between infection and (auto)immunity. Hsp have been associated with atherosclerosis for a long time now [73]. Immunization with hsp65 in New Zealand White rabbits leads to the formation of atherosclerotic lesions. Moreover, T-cells specific for hsp65 were found to be present in the lesions not only of hsp65 immunized rabbits, but also rabbits fed a cholesterol rich diet, which suggest that, at least in this model, heat shock proteins could be involved in T cell mediated plaque inflammation [74]. Serological studies have also implicated a role for hsp in human atherosclerosis. Antibody titers against hsp60, the human homologue of mycobacterial hsp65, are associated with the presence and severity of coronary artery disease. Specific responses of plaque derived T-cells against human hsp60 have been reported [65]. Furthermore, it is interestingly to note that the responses of T-cells against Cp and P. gingivalis are (at least) partially also directed against the respective bacterial hsp [65,70].


   4. Conclusions
Top
 1. Introduction
 2. T-cell immune responses...
 3. T-cells and initiators...
 4. Conclusions
References
 
Current knowledge on atherogenesis indicates a central role for inflammatory pathways in plaque development and also in the onset of clinically manifest thrombotic complications. This review focused only on adaptive immune responses in plaques, and particularly on the role of T-cells as immune regulatory cells herein. Undoubtly these T cell mediated immune responses represent only part of the complex inflammatory pathways. For example, several interactions between native and adaptive immune responses occur in lesions, and in both instances other mononuclear cells, macrophages, exert most important effector functions in inflammation. Moreover, there is a lot of evidence that products of lipid metabolism inside the plaque serve as a major trigger of different types of inflammatory responses (innate and adaptive). However, infectious agents could serve as additional triggers and so introduce episodes of accelerated plaque inflammation. For example, increased numbers of activated T-cells [31], circulating Cp positive T-cells [75] and Cp containing plaques [59] have all been detected in patients with ischemic coronary syndromes. And not only Cp, but also several other common infectious agents may follow the same pathway, as is illustrated in Fig. 4. T-cells that bear antigen specificity for common infectious pathogens continuously recirculate in the peripheral blood. Some of these may be recruited in atherosclerotic lesions, a process mediated by adhesion molecules and chemokines produced by inflammatory cells in the inflamed plaque. Similarly, mononuclear cells harboring infectious pathogens can migrate into the plaque. These are macrophages (for example with components of C. pneumoniae, P. gingivalis or other infectious pathogens) or EBV infected B-cells. When T-cells encounter their respective antigen inside the plaque they will respond by clonal proliferation and cytokine production, which in turn activates other plaque cells, particularly macrophages. On this basis we could speculate that plaque inflammatory activity increases periodically, and more frequently throughout the lifetime of a plaque when more pathogens and their respective specific T-cells are involved. In fact, evidence for a similar contributory role of micro organisms to the inflammatory burden is presently also emerging for other chronic inflammatory diseases, such as rheumatoid arthritis [76–78] and skin ulcers [79]. Therefore we anticipate that much can be learnt from a full dissection the antigenic repertoire of T-cells in human plaques.


Figure 4
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  		Fig. 4 Schematic presentation of T cell influx, antigen presentation and antigen specific T cell activation in atherosclerotic plaques. For explanation see text.

 


   Notes
 
Time for primary review 32 days.


   References
Top
 1. Introduction
 2. T-cell immune responses...
 3. T-cells and initiators...
 4. Conclusions
 References
 

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