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Regulatory T lymphocytes in myocardial infarction: A promising new therapeutic target
International Journal of Cardiology 203 (2016) 923–928
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Regulatory T lymphocytes in myocardial infarction: A promising new therapeutic target Ya-ping Wang a, Yao Xie b, Hong Ma c, Sheng-an Su a, Yi-dong Wang a, Jian-an Wang a, Mei-xiang Xiang a,⁎ a b c
Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Cardiovascular Key Lab of Zhejiang Province, #88 Jiefang Road, Hangzhou, Zhejiang, 310009, China Cardiovascular Division, King's College London BHF Center, London, United Kingdom McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
a r t i c l e
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Article history: Received 29 August 2015 Received in revised form 21 October 2015 Accepted 8 November 2015 Available online 10 November 2015 Keywords: Regulatory T lymphocyte Myocardial infarction Plaque instability Ischemia-reperfusion injury Ventricular remodeling
a b s t r a c t Myocardial infarction (MI) is one of the leading causes of death especially in developed countries. Although the advent of early myocardial reperfusion therapy contributes to decreasing the mortality of patients with MI, cardiac ischemia-reperfusion injury and adverse remodeling during the repair process still remain the major factors impairing cardiac function and resulting in unsatisfactory prognosis. Excessive inflammation and immune responses play a crucial role during the whole process of MI. Regulatory T lymphocytes, characterized by immunosuppressive capacity, are associated with many immune-related diseases. Recent studies have proven a protective role of regulatory T cells in MI, which is mainly achieved by modulating inflammation and immune responses. In this review, we will summarize current knowledge of regulatory T lymphocytes, and highlight their roles in the onset of MI, ischemia-reperfusion injury, as well as post-infarct cardiac healing and remodeling. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Myocardial infarction (MI) refers to cardiac ischemic necrosis arising from a sudden reduction of oxygen supply from coronary arteries with severe stenosis or obstruction. Due to the high morbidity and mortality, MI has become one of the most concerning health issues in the modern society [1]. Fortunately, with the advent of early myocardial reperfusion such as percutaneous coronary intervention and thrombolytic therapy, the mortality has been decreasing over the past decades [2]. Nevertheless, reperfusion therapy per se unwantedly causes another kind of injury called ischemia-reperfusion injury (IRI), which undermines the full benefits of reperfusion therapy and there is still no effective treatment [3]. In addition, the number of the patients with heart failure after MI has increased, which mostly results from adverse ventricular remodeling [4], making the patients exposed to a higher risk of further cardiovascular events than others. Thus, it still remains a great challenge to work out an effective management for MI. Previous studies indicated that inflammatory responses are critically involved in MI. Necrotic cardiomyocytes release large quantities of intracellular contents, triggering an immense inflammatory cascade [5]. The inflammatory process helps to clear dead cells and promote scar formation, preventing the heart from rupture; however, excessive ⁎ Corresponding author at: Second Affiliated Hospital of Zhejiang University School of Medicine, Cardiovascular Key Lab of Zhejiang Province, #88 Jiefang Road, Hangzhou, Zhejiang 310009, China. E-mail address: [email protected] (M. Xiang).
http://dx.doi.org/10.1016/j.ijcard.2015.11.078 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
inflammation leads to degradation of extracellular matrix and apoptosis of cardiomyocytes, resulting in ventricular remodeling and heart failure [6]. Hence timely control of the post-infarct inflammation may be an effective approach for treating MI. In the past decades, regulatory T lymphocytes (Tregs), characterized by negatively regulating inflammation and immune responses, have drawn great attention in many disorders including autoimmune diseases [7], cancer [8], infective diseases [9], allograft rejection [10] and ischemic diseases [11]. Recently, increasing evidence has demonstrated the involvement of Tregs in MI (see Table 1). Patients with acute coronary syndrome (ACS) exhibit a significant down-regulation in the frequency and function of peripheral Tregs compared with patients with stable angina and normal artery subjects [12]. And infusion of Tregs into murine MI models can reduce the infarct size and attenuate MIinduced cardiac dysfunction [13]. This review will respectively discuss the roles of Tregs in the onset of MI, myocardial IRI, as well as cardiac repair and remodeling process after MI. 2. General knowledge of Tregs Regulatory T cells, once named as suppressor T cells [14], are a specific subset of T lymphocytes with immunosuppressive capacity. It is estimated that, under physiological conditions, the population of Tregs occupies 5–10% of CD4+ T cells in human peripheral blood [15]. Tregs comprise two subsets: naturally-occurring Tregs (nTregs) and induced Tregs (iTregs) [16]. The former subpopulation develops in the
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Table 1 Major findings on Tregs in clinical and experimental studies. Findings on Tregs Humans The frequency and suppressive ability of peripheral CD4+ CD25+ Tregs were down-regulated in patients with ACS compared with patients with stable angina and normal coronary artery subjects. The percentages of both CD27+ Tregs and CD27− Tregs were lower in patients with STEMI compared with normal controls, and the ratio of the two subsets was skewed towards the less suppressive CD27− Tregs. Decreased number of Tregs was shown in vulnerable atherosclerotic lesions than in stable lesions. Low levels of baseline circulating CD4+ Foxp3+ T cells were related with higher risk for development of MI. The production of Tregs by thymus was attenuated in patients with NSTEACS compared with patients with stable angina and patients with chest pain syndrome, as indicated by lower frequency of peripheral recent thymic emigrant Treg cells (CD4+ CD25+ CD127low CD45RO− CD45RA+ CD31+ Tregs). The circulating apoptotic Tregs (CD4+ CD25+ CD127low annexin-V+ 7-AAD− Tregs) was significantly higher in patients with NSTEACS than in patients with stable angina and patients with chest pain syndrome. Recruitment of Tregs was found in post-infarct hearts of mice. Mice Expansion of Tregs by using IL-2/anti-IL-2 complex increased the stability of atherosclerotic plaques. Partial depletion of Tregs by before ischemia-reperfusion by using anti-CD25 monoclonal antibodies exacerbated IRI, while adoptive transfer of Tregs alleviated IRI. The protection of rosuvastatin against myocardial IRI was partially mediated by immunosuppression of Tregs. Expansion of Tregs in vivo by both adoptive transfer and administration of CD28 superagonistic antibody improved ventricular contractility and attenuated remodeling, while Treg depletion by anti-CD25 antibodies contributes to early post-infarct dilation and increased left ventricular end-diastolic volume.
References Adi et al. [12]
Gennaro et al. [28]
Dietel et al. [39] de Boer et al. [40] Wigren et al. [29]
Zhang et al. [30]
Zhang et al. [30]
Saxena et al. [32] Foks et al. [41]
Fleming et al. [44] Linfert et al. [45]
and their deficiency or dysfunction leads to certain kinds of immunerelated diseases, such as systemic lupus erythematosus and rheumatoid arthritis [16,25]. On the whole, the mechanisms underlying Treg-mediated immune suppression include secretion of anti-inflammatory cytokines and cellcontact-dependent interaction with other cell types [20](see Fig. 1d). Some studies demonstrated that nTregs exerted immune suppression via cell–cell contact, whereas Tr1 cells inhibited immune responses through secreting IL-10 and transforming growth factor (TGF)-β [26], and the function of Th3 cells was TGF-β dependent [27]. 3. Potential peripheral Tregs defect in MI Numerical and functional alterations of Tregs have been reported in patients with MI. Adi Mor and colleagues first demonstrated a significant reduction in the frequency of peripheral CD4+ CD25+ Tregs in patients with ACS, compared with patients who suffered from stable angina and normal coronary artery subjects. In addition, Tregs derived from patients with ACS were severely compromised in their ability to suppress responder CD4+ CD25− T cell proliferation [12]. Similarly, another study demonstrated that the percentages of circulating CD27+ Tregs and CD27− Tregs were both decreased in patients with STsegment elevation myocardial infarction (STEMI) compared with normal controls. In addition, the ratio of these two subsets was skewed towards the less suppressive CD27− Tregs [28]. The association between Tregs and MI was further supported by a prospective study by Maria Wigren et al. [29]. They addressed that low levels of baseline circulating CD4+ Foxp3+ T cells were linked to higher risk for development of MI, suggesting that Tregs might play a protective role in MI and represent an attractive therapeutic target. However, the relation between levels of Tregs and the severity and prognosis of patients with MI is to be elucidated. 4. Possible mechanisms underlying peripheral Tregs defect in MI
Ke et al. [50]
Matsumoto et al. [13] Saxena et al. [32] Tang et al. [54]
Treg — regulatory T lymphocyte; ACS — acute coronary syndrome; STEMI — ST-segment elevation myocardial infarction; MI — myocardial infarction; NSTEACS — non-ST-segment elevation acute coronary syndrome; IRI — ischemia-reperfusion injury.
thymus, and is identified by co-expression of CD4, CD25 and fork head box P3 (Foxp3) [17]. Induced Tregs include type 1 regulatory T (Tr1) cells [18], T helper-3 (Th3) regulatory cells [19] and CD8+ Foxp3+ Tregs [20], and are differentiated from naive CD4+ T cells in periphery lymphoid organs when exposed to particular stimulations, such as interleukin (IL)-10, interferon (IFN)-α and oral administration of antigen [14,21] (see Fig. 1a, b). Both of these two subsets of Tregs have immunosuppressive capacity. They play roles in inhibiting the proliferation of CD4+ and CD8+ T cells and their production of IFN-γ [18], suppressing the maturation and function of dendritic cells (DC) [22], enhancing differentiation of anti-inflammatory M2 macrophage [23] and reducing the secretion of pro-inflammatory cytokines by monocytes [23]. Even an ‘inverted pyramid’ model was proposed by Vicente Bodi to describe the interactions between Tregs and other cell types. This model demonstrated that a few Tregs, at the bottom of the inverted pyramid, control the upper parts containing neutrophils, monocytes, effector T lymphocytes etc. [24]. Through inhibiting both innate and adaptive immune responses, Tregs play a crucial role in the maintenance of immunologic homeostasis,
The possible causes of the reduction in circulating Tregs number during MI include impaired output from thymus, increased apoptosis and trafficking of peripheral Tregs to inflammatory sites. The frequency of recent thymic emigrant Treg cells (indicated as CD4+ CD25+ CD127lowCD45RO− CD45RA+ CD31+ Tregs) in peripheral blood was lower in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) than in patients with chronic stable angina (CSA) and patients with chest pain syndrome (CPS), suggesting that the production of Tregs by thymus was attenuated in NSTEACS patients [30]. This was further supported by the observation that intracellular T cell receptor excision circle (TREC) level, a marker of newly generated T cells, was markedly lower in Tregs from NSETACS patients [30]. Increased apoptosis of Tregs also partially accounts for peripheral Tregs defect in NSTEACS patients [30]. The number of circulating CD4+ CD25+ CD127low annexin-V+ 7-AAD− Tregs, which represented apoptotic Tregs, was significantly higher in NSTEACS patients than in CSA and CPS patients. Besides, higher expression of proapoptotic gene Bak and lower expression of antiapoptotic gene Bcl-2 were shown in purified Tregs from patients with NSTEACS. The apoptosis might be spontaneous or induced by increased plasma level of oxidized low density lipoprotein (LDL) in patients. It has been well documented that certain subsets of Tregs can migrate into inflamed tissues to limit the inflammatory responses [31]. Emerging evidence has shown the recruitment of Tregs in post-infarct hearts of mice [32]. This gave rise to the notion that Tregs probably trafficked from peripheral blood circulation to inflammatory hearts, leading to the reduction in circulating Tregs (see Fig. 1c). This is probably mediated by specific chemokine receptors (CCRs) expressed on the surface of Tregs. These CCRs interact with inflammatory cytokines secreted by antigen-presenting cells, including neutrophils, macrophages, activated T cells etc., guiding Tregs into inflammatory sites [33]. It has
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Fig. 1. The development of Tregs and the underlying mechanisms of Treg-mediated immunosuppression. (a) Naturally-occurring Tregs (nTregs) are differentiated from CD4+ CD8− thymocytes in the thymus. (b) Induced Tregs (iTregs), including type 1 regulatory T cells (Tr1) and T helper-3 regulatory cells (Th3), are differentiated from naïve CD4+ T lymphocytes in peripheral lymphoid organs when exposed to particular stimulations such as interleukin-10 and myelin basic protein. (c) Circulating Tregs migrate from peripheral blood circulation to inflammatory hearts. (d) The underlying mechanisms of Treg-mediated immune suppression include secretion of anti-inflammatory cytokines and cell-contact-dependent interaction with other cell types.
been reported that CCR5 knockout leads to impaired recruitment of Tregs, enhanced inflammation and adverse remodeling in the infarcted mouse myocardium [34]. Lovastatin induces the recruitment of Tregs via up-regulation of CCR1 in a murine skin delayed-type hypersensitivity model [35]. Besides, CCR2 and CCR4 were also proven in other models to have the capacity to guide Tregs into inflammatory sites [36,37]. 5. Role of Tregs in the onset of MI Rupture or erosion of the destabilized atherosclerotic plaque and subsequent coronary thrombotic occlusion or spasm are the pathologic basis of acute MI [38]. Recent studies have revealed that Tregs contributed to the stability of atherosclerotic lesion. Decreased number of Tregs was shown in human vulnerable atherosclerotic lesions than in stable lesions [39,40]. Expansion of Tregs by using IL-2/anti-IL-2 complex in LDL-receptor knockout (LDL−/−) mice with well-established atherosclerosis showed an increased stability indicated by enhanced collagen content in the lesions [41]. Correspondingly, Xiao Meng and colleagues also discovered a declined disruption rate of the carotid atherosclerotic plaques in a dose-dependent manner after adoptive transfer of Tregs to apolipoprotein E knockout (ApoE−/−) mice. The results showed a significant increase of smooth muscle cells and collagen as well as a substantial decrease of macrophage and lipids content in the lesions [42]. Tregs probably stabilize the atherosclerotic plaques through reducing production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, inhibiting expression of matrix metalloproteinase (MMP)-2 and MMP-9, and enhancing expression of prolyl-4-hydroxylase α1 which determines the maturation and synthesis of collagens. This effect was largely mediated by TGF-β and IL-10 [42]. In addition, Tregs inhibit the migration and adhesion capacity of mature DCs, preventing their recruitment into atherosclerotic lesions and stimulation of effector T cells
[39]. These discoveries indicated a patent therapy to stabilize plaques and thus to prevent the development of acute MI. 6. Role of Tregs in myocardial IRI Myocardial reperfusion therapy is a great milestone in the management of MI. However, reperfusion injury diminishes the full benefits of reperfusion therapy and therefore tempers its further progress [3]. This reperfusion injury contributes to myocardial stunning, no-reflow phenomenon, arrhythmia and cardiomyocyte death [43]. Minimizing IRI is of great significance in improving the efficacy of reperfusion therapies. The pathogenesis of myocardial IRI is multi-factorial, however, it is well established that innate and adaptive immunity plays an essential role in mediating IRI [44,45]. Recently, accumulating evidence has indicated that Tregs do protect multiple organs, such as intestine, liver, kidney etc., from IRI by regulating immune and inflammatory responses [46–48]. Partial depletion of Tregs in mice before ischemiareperfusion by using anti-CD25 monoclonal antibodies (PC61) exacerbated IRI, and further enhanced the accumulation of inflammatory cells such as neutrophils, CD4+ T cells and the production of inflammatory cytokines, including TNF-α and IFN-γ. In contrast, adoptive transfer of Tregs attenuated IRI and alleviated tissue inflammatory state [46,47]. Investigation on the role of Tregs in myocardial IRI is quite limited. As we know, numerous adjuvant therapeutic strategies help to attenuate myocardial IRI, mainly including pharmacological interventions and ischemic conditioning [49]. Recent experimental studies have illustrated an involvement of Tregs in some pharmacological interventions adjuvant to reperfusion treatment. One study [50] demonstrated that pretreatment with rosuvastatin before myocardial ischemiareperfusion attenuated cardiac injury, reduced inflammatory cell infiltration, as well as enhanced the accumulation of Tregs in the heart. Moreover, the number of infiltrated inflammatory cells in myocardium was inversely related to the number of Tregs, suggesting the cardiac
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protection against IRI by rosuvastatin was partially mediated by immunosuppression of Tregs. Pretreatment with FTY720, an analog of sphingosine-1-phosphate, also has a protective effect on mouse myocardial IRI [51]. And it is confirmed that FTY720 has the ability to induce functional activity of Tregs [52]. But whether Tregs play a role in FTY720-mediated cardiac protection against IRI needs further elucidation. In addition, it demands further efforts to investigate whether Tregs are associated with other adjuvant therapies to myocardial reperfusion treatment, such as ischemic conditioning and heat preconditioning. Together, these findings indicated that strategies targeting expanding Tregs in vivo could be promising in attenuating myocardial IRI.
7. Role of Tregs in the repair and remodeling after MI The ischemic heart undergoes a series of compensatory changes in ventricular size, shape and function to maintain sufficient cardiac output required by human body. This pathological process is called ventricular remodeling [53], mainly manifested as ventricular hypertrophy and dilation. Nevertheless, persistent or exaggerated inflammatory reaction during MI enhances degradation of extracellular matrix, increases ardiomyocyte apoptosis, and promotes interstitial fibrosis. Those processes lead to adverse ventricular remodeling, which represents maladaptive repair and is the major mechanism of heart failure [13]. Therefore, restraining excessive inflammation is important in attenuating adverse remodeling and improving cardiac healing after MI. Increasing evidence indicated the involvement of Tregs in cardiac healing process after MI [13,32,54]. Expansion of Tregs in vivo by both adoptive transfer of CD4+ CD25+ Tregs and administration of CD28 super agonistic antibody (JJ316) improves ventricular contractility and attenuates MI-induced remodeling as indicated by reduced interstitial fibrosis, impaired MMP activity and decreased cardiomyocyte apoptosis
[13,54]. In contrast, Treg depletion by PC61 contributes to early postinfarct dilation and increased left ventricular end-diastolic volume [32]. Mechanistically, on the one hand, Tregs inhibit the recruitment of pro-inflammatory cells including neutrophils, monocytes, CD4+ T lymphocytes etc. into post-infarct hearts and suppress the local expression of inflammatory cytokines including TNF-α, IL-1β etc. [54] (see Fig. 2). Tingting Tang also demonstrated that Tregs inhibited the cytotoxicity of CD8+ T lymphocytes to cardiomyocytes in vitro and restrained their proliferation in vivo [54]. It is well established that upon infiltration into inflammatory tissue, monocytes differentiate into two distinct macrophage phenotypes: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages [55]. Johannes Weirather et al. [56] demonstrated that modulating the process of macrophage differentiation by Tregs was probably one of the mechanisms responsible for their protection against adverse remodeling after MI. They found depletion of Tregs before MI by using Foxp3DTR mice or PC61 administration promoted M1-like macrophage polarization, while Treg activation using superagonistic CD28-specific monoclonal antibodies induced M2-like macrophage differentiation (see Fig. 2). On the other hand, Tregs participate in promoting post-infarct cardiac repair also by affecting reparative immune cells involved in MI. Fibroblasts/myofibroblasts play a pivotal role in repair of injured myocardium with the main function of secreting collagen, which is the major component of extracellular matrix (ECM) [57]. However, persistent activation of myofibroblasts promotes fibrosis and adverse ventricular remodeling. Amit Saxena et al. [32] demonstrated that in vitro, Tregs had the ability to modulate the phenotype and function of cardiac fibroblasts. The cardiac fibroblasts co-cultured with Tregs exhibited a reduction of α-smooth muscle actin expression, decreased expression of MMP-3, and marked attenuation of gel contraction, suggesting compromised transdifferentiation of myofibroblasts. In addition, the co-culture system also showed decreased expression of MMPs, which function as degrading ECM. Regulation of the
Fig. 2. Tregs are involved in the repair and remodeling process after myocardial infarction through infecting different types of cells. They can inhibit the recruitment of inflammatory cells (neutrophils, monocytes, CD4+ T lymphocytes etc.) into post-infarct hearts, skew the ratio of macrophage 1/macrophage 2 towards macrophage 2, inhibit the transdifferentiation of fibroblasts into myofibroblasts, and prevent the apoptosis of cardiomyocytes.
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phenotype and function of fibroblasts/myofibroblasts probably makes a contribution to the beneficial effect of Tregs on post-MI remodeling (see Fig. 2). Interestingly, besides affecting immune cells, Tregs may also exert beneficial effect on post-infarct remodeling through direct protection of cardiomyocytes. Tregs protected co-cultured neonatal rat cardiomyocytes from lipopolysaccharide (LPS)-induced apoptosis by IL-10 as well as direct cell–cell contact (see Fig. 2). Tregs also reduced the production of pro-inflammatory cytokines (TNF-α, IL-1β) by cardiomyocytes stimulated by LPS [54]. In conclusion, these findings indicate promising therapeutic value of Tregs in attenuating post-MI remodeling and thus improving the prognosis of patients with MI. However, more detailed mechanisms accounting for how Tregs affect the immune cells and whether interaction between Tregs and other cell types is associated with post-MI remodeling are still not fully understood.
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transfer of Tregs that are capable of trafficking into inflammatory hearts may be more effective. Thus, it still requires further studies to successfully transform expansion of Tregs into a clinical effective therapy for MI. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgment This work was supported by grants from the National Natural Science Foundation of China (No. 81270179 and No. 81470384 to Mei-xiang Xiang).
8. Summary References Tregs, a specific immunosuppressive subset of T cells, has been indicated to have beneficial effect on numerous diseases, including rheumatoid arthritis [58], systemic lupus erythematosus [59], colitis [60] and atherosclerosis [20]. It is firmly established that inflammation and immune responses are crucially involved in MI. Recently, compelling evidence has demonstrated that Tregs also play a protective role in the onset of MI, myocardial IRI and post-infarct remodeling process by inhibiting undesired inflammatory responses. Moreover, smoking is considered one of the main risk factors for developing coronary heart disease, but disappointingly, the introduction of the smoking ban in Malta exhibited no immediate or significant reduction in the admission rate and mortality of ACS [61]. This could be due to lack of proper enforcement of the ban or inadequate awareness regarding the bad effects of smoking. There was one study suggested that the proportions of subpopulations of Tregs were altered in the blood and bronchoalveolar lavage samples of smokers with normal pulmonary function and patients with chronic obstructive pulmonary disease compared with non-smokers [62]. This indicated a possible involvement of Tregs in smoking-related diseases, and Tregs might be a more feasible and effective therapeutic target than smoking ban legislation in these diseases. This arises our great interest to verify whether Tregs play a role in smoking-induced coronary atherosclerosis in the following research. Although numerous studies suggested expansion and activation of Tregs might be a promising new strategy for preventing and treating MI, there are still some essential problems to overcome before clinical application. One problem is the difficulty in identifying Tregs. Different methods of defining Tregs may partially bear responsibility for some conflicting results in different studies, and expression of CD25 and Foxp3 is also found in activated conventional CD4+ T cells [29]. To better understand the function of Tregs, more specific identification should be explored. Another problem is how to expand Tregs in vivo. In brief, there are two ways by which we can increase the number of Tregs: one is to induce the differentiation of Tregs from naive precursors by administrating particular agents; the other is adoptive transfer of Tregs isolated from human peripheral blood and expanded ex vivo [15,21]. Certain kinds of agents, such as IL-2/anti-IL-2 complex, have been reported in animal experiments with the ability to expand Tregs in vivo [63], enabling them to attenuate inflammation-induced injuries [64]. However, their safety and efficacy in human needs further elucidation. In addition, a larger fraction of the injected Tregs was found located in the spleen than in the heart [13]. As reviewed by Jochen Huehn and Alf Hamann [31], migration and localization also influence the suppressive capacity of Tregs: some subsets of Tregs are recruited in lymphoid tissue to suppress the initiation of immune responses, and other subsets enter inflammatory sites to restrain established immune reaction. The different homing preferences are dependent on molecules expressed on the surface of different subsets of Tregs. For MI patients, adoptive
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Review
Regulatory T lymphocytes in myocardial infarction: A promising new therapeutic target Ya-ping Wang a, Yao Xie b, Hong Ma c, Sheng-an Su a, Yi-dong Wang a, Jian-an Wang a, Mei-xiang Xiang a,⁎ a b c
Department of Cardiology, Second Affiliated Hospital of Zhejiang University School of Medicine, Cardiovascular Key Lab of Zhejiang Province, #88 Jiefang Road, Hangzhou, Zhejiang, 310009, China Cardiovascular Division, King's College London BHF Center, London, United Kingdom McAllister Heart Institute, University of North Carolina, Chapel Hill, NC 27599, USA
a r t i c l e
i n f o
Article history: Received 29 August 2015 Received in revised form 21 October 2015 Accepted 8 November 2015 Available online 10 November 2015 Keywords: Regulatory T lymphocyte Myocardial infarction Plaque instability Ischemia-reperfusion injury Ventricular remodeling
a b s t r a c t Myocardial infarction (MI) is one of the leading causes of death especially in developed countries. Although the advent of early myocardial reperfusion therapy contributes to decreasing the mortality of patients with MI, cardiac ischemia-reperfusion injury and adverse remodeling during the repair process still remain the major factors impairing cardiac function and resulting in unsatisfactory prognosis. Excessive inflammation and immune responses play a crucial role during the whole process of MI. Regulatory T lymphocytes, characterized by immunosuppressive capacity, are associated with many immune-related diseases. Recent studies have proven a protective role of regulatory T cells in MI, which is mainly achieved by modulating inflammation and immune responses. In this review, we will summarize current knowledge of regulatory T lymphocytes, and highlight their roles in the onset of MI, ischemia-reperfusion injury, as well as post-infarct cardiac healing and remodeling. © 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Myocardial infarction (MI) refers to cardiac ischemic necrosis arising from a sudden reduction of oxygen supply from coronary arteries with severe stenosis or obstruction. Due to the high morbidity and mortality, MI has become one of the most concerning health issues in the modern society [1]. Fortunately, with the advent of early myocardial reperfusion such as percutaneous coronary intervention and thrombolytic therapy, the mortality has been decreasing over the past decades [2]. Nevertheless, reperfusion therapy per se unwantedly causes another kind of injury called ischemia-reperfusion injury (IRI), which undermines the full benefits of reperfusion therapy and there is still no effective treatment [3]. In addition, the number of the patients with heart failure after MI has increased, which mostly results from adverse ventricular remodeling [4], making the patients exposed to a higher risk of further cardiovascular events than others. Thus, it still remains a great challenge to work out an effective management for MI. Previous studies indicated that inflammatory responses are critically involved in MI. Necrotic cardiomyocytes release large quantities of intracellular contents, triggering an immense inflammatory cascade [5]. The inflammatory process helps to clear dead cells and promote scar formation, preventing the heart from rupture; however, excessive ⁎ Corresponding author at: Second Affiliated Hospital of Zhejiang University School of Medicine, Cardiovascular Key Lab of Zhejiang Province, #88 Jiefang Road, Hangzhou, Zhejiang 310009, China. E-mail address: [email protected] (M. Xiang).
http://dx.doi.org/10.1016/j.ijcard.2015.11.078 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
inflammation leads to degradation of extracellular matrix and apoptosis of cardiomyocytes, resulting in ventricular remodeling and heart failure [6]. Hence timely control of the post-infarct inflammation may be an effective approach for treating MI. In the past decades, regulatory T lymphocytes (Tregs), characterized by negatively regulating inflammation and immune responses, have drawn great attention in many disorders including autoimmune diseases [7], cancer [8], infective diseases [9], allograft rejection [10] and ischemic diseases [11]. Recently, increasing evidence has demonstrated the involvement of Tregs in MI (see Table 1). Patients with acute coronary syndrome (ACS) exhibit a significant down-regulation in the frequency and function of peripheral Tregs compared with patients with stable angina and normal artery subjects [12]. And infusion of Tregs into murine MI models can reduce the infarct size and attenuate MIinduced cardiac dysfunction [13]. This review will respectively discuss the roles of Tregs in the onset of MI, myocardial IRI, as well as cardiac repair and remodeling process after MI. 2. General knowledge of Tregs Regulatory T cells, once named as suppressor T cells [14], are a specific subset of T lymphocytes with immunosuppressive capacity. It is estimated that, under physiological conditions, the population of Tregs occupies 5–10% of CD4+ T cells in human peripheral blood [15]. Tregs comprise two subsets: naturally-occurring Tregs (nTregs) and induced Tregs (iTregs) [16]. The former subpopulation develops in the
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Table 1 Major findings on Tregs in clinical and experimental studies. Findings on Tregs Humans The frequency and suppressive ability of peripheral CD4+ CD25+ Tregs were down-regulated in patients with ACS compared with patients with stable angina and normal coronary artery subjects. The percentages of both CD27+ Tregs and CD27− Tregs were lower in patients with STEMI compared with normal controls, and the ratio of the two subsets was skewed towards the less suppressive CD27− Tregs. Decreased number of Tregs was shown in vulnerable atherosclerotic lesions than in stable lesions. Low levels of baseline circulating CD4+ Foxp3+ T cells were related with higher risk for development of MI. The production of Tregs by thymus was attenuated in patients with NSTEACS compared with patients with stable angina and patients with chest pain syndrome, as indicated by lower frequency of peripheral recent thymic emigrant Treg cells (CD4+ CD25+ CD127low CD45RO− CD45RA+ CD31+ Tregs). The circulating apoptotic Tregs (CD4+ CD25+ CD127low annexin-V+ 7-AAD− Tregs) was significantly higher in patients with NSTEACS than in patients with stable angina and patients with chest pain syndrome. Recruitment of Tregs was found in post-infarct hearts of mice. Mice Expansion of Tregs by using IL-2/anti-IL-2 complex increased the stability of atherosclerotic plaques. Partial depletion of Tregs by before ischemia-reperfusion by using anti-CD25 monoclonal antibodies exacerbated IRI, while adoptive transfer of Tregs alleviated IRI. The protection of rosuvastatin against myocardial IRI was partially mediated by immunosuppression of Tregs. Expansion of Tregs in vivo by both adoptive transfer and administration of CD28 superagonistic antibody improved ventricular contractility and attenuated remodeling, while Treg depletion by anti-CD25 antibodies contributes to early post-infarct dilation and increased left ventricular end-diastolic volume.
References Adi et al. [12]
Gennaro et al. [28]
Dietel et al. [39] de Boer et al. [40] Wigren et al. [29]
Zhang et al. [30]
Zhang et al. [30]
Saxena et al. [32] Foks et al. [41]
Fleming et al. [44] Linfert et al. [45]
and their deficiency or dysfunction leads to certain kinds of immunerelated diseases, such as systemic lupus erythematosus and rheumatoid arthritis [16,25]. On the whole, the mechanisms underlying Treg-mediated immune suppression include secretion of anti-inflammatory cytokines and cellcontact-dependent interaction with other cell types [20](see Fig. 1d). Some studies demonstrated that nTregs exerted immune suppression via cell–cell contact, whereas Tr1 cells inhibited immune responses through secreting IL-10 and transforming growth factor (TGF)-β [26], and the function of Th3 cells was TGF-β dependent [27]. 3. Potential peripheral Tregs defect in MI Numerical and functional alterations of Tregs have been reported in patients with MI. Adi Mor and colleagues first demonstrated a significant reduction in the frequency of peripheral CD4+ CD25+ Tregs in patients with ACS, compared with patients who suffered from stable angina and normal coronary artery subjects. In addition, Tregs derived from patients with ACS were severely compromised in their ability to suppress responder CD4+ CD25− T cell proliferation [12]. Similarly, another study demonstrated that the percentages of circulating CD27+ Tregs and CD27− Tregs were both decreased in patients with STsegment elevation myocardial infarction (STEMI) compared with normal controls. In addition, the ratio of these two subsets was skewed towards the less suppressive CD27− Tregs [28]. The association between Tregs and MI was further supported by a prospective study by Maria Wigren et al. [29]. They addressed that low levels of baseline circulating CD4+ Foxp3+ T cells were linked to higher risk for development of MI, suggesting that Tregs might play a protective role in MI and represent an attractive therapeutic target. However, the relation between levels of Tregs and the severity and prognosis of patients with MI is to be elucidated. 4. Possible mechanisms underlying peripheral Tregs defect in MI
Ke et al. [50]
Matsumoto et al. [13] Saxena et al. [32] Tang et al. [54]
Treg — regulatory T lymphocyte; ACS — acute coronary syndrome; STEMI — ST-segment elevation myocardial infarction; MI — myocardial infarction; NSTEACS — non-ST-segment elevation acute coronary syndrome; IRI — ischemia-reperfusion injury.
thymus, and is identified by co-expression of CD4, CD25 and fork head box P3 (Foxp3) [17]. Induced Tregs include type 1 regulatory T (Tr1) cells [18], T helper-3 (Th3) regulatory cells [19] and CD8+ Foxp3+ Tregs [20], and are differentiated from naive CD4+ T cells in periphery lymphoid organs when exposed to particular stimulations, such as interleukin (IL)-10, interferon (IFN)-α and oral administration of antigen [14,21] (see Fig. 1a, b). Both of these two subsets of Tregs have immunosuppressive capacity. They play roles in inhibiting the proliferation of CD4+ and CD8+ T cells and their production of IFN-γ [18], suppressing the maturation and function of dendritic cells (DC) [22], enhancing differentiation of anti-inflammatory M2 macrophage [23] and reducing the secretion of pro-inflammatory cytokines by monocytes [23]. Even an ‘inverted pyramid’ model was proposed by Vicente Bodi to describe the interactions between Tregs and other cell types. This model demonstrated that a few Tregs, at the bottom of the inverted pyramid, control the upper parts containing neutrophils, monocytes, effector T lymphocytes etc. [24]. Through inhibiting both innate and adaptive immune responses, Tregs play a crucial role in the maintenance of immunologic homeostasis,
The possible causes of the reduction in circulating Tregs number during MI include impaired output from thymus, increased apoptosis and trafficking of peripheral Tregs to inflammatory sites. The frequency of recent thymic emigrant Treg cells (indicated as CD4+ CD25+ CD127lowCD45RO− CD45RA+ CD31+ Tregs) in peripheral blood was lower in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS) than in patients with chronic stable angina (CSA) and patients with chest pain syndrome (CPS), suggesting that the production of Tregs by thymus was attenuated in NSTEACS patients [30]. This was further supported by the observation that intracellular T cell receptor excision circle (TREC) level, a marker of newly generated T cells, was markedly lower in Tregs from NSETACS patients [30]. Increased apoptosis of Tregs also partially accounts for peripheral Tregs defect in NSTEACS patients [30]. The number of circulating CD4+ CD25+ CD127low annexin-V+ 7-AAD− Tregs, which represented apoptotic Tregs, was significantly higher in NSTEACS patients than in CSA and CPS patients. Besides, higher expression of proapoptotic gene Bak and lower expression of antiapoptotic gene Bcl-2 were shown in purified Tregs from patients with NSTEACS. The apoptosis might be spontaneous or induced by increased plasma level of oxidized low density lipoprotein (LDL) in patients. It has been well documented that certain subsets of Tregs can migrate into inflamed tissues to limit the inflammatory responses [31]. Emerging evidence has shown the recruitment of Tregs in post-infarct hearts of mice [32]. This gave rise to the notion that Tregs probably trafficked from peripheral blood circulation to inflammatory hearts, leading to the reduction in circulating Tregs (see Fig. 1c). This is probably mediated by specific chemokine receptors (CCRs) expressed on the surface of Tregs. These CCRs interact with inflammatory cytokines secreted by antigen-presenting cells, including neutrophils, macrophages, activated T cells etc., guiding Tregs into inflammatory sites [33]. It has
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Fig. 1. The development of Tregs and the underlying mechanisms of Treg-mediated immunosuppression. (a) Naturally-occurring Tregs (nTregs) are differentiated from CD4+ CD8− thymocytes in the thymus. (b) Induced Tregs (iTregs), including type 1 regulatory T cells (Tr1) and T helper-3 regulatory cells (Th3), are differentiated from naïve CD4+ T lymphocytes in peripheral lymphoid organs when exposed to particular stimulations such as interleukin-10 and myelin basic protein. (c) Circulating Tregs migrate from peripheral blood circulation to inflammatory hearts. (d) The underlying mechanisms of Treg-mediated immune suppression include secretion of anti-inflammatory cytokines and cell-contact-dependent interaction with other cell types.
been reported that CCR5 knockout leads to impaired recruitment of Tregs, enhanced inflammation and adverse remodeling in the infarcted mouse myocardium [34]. Lovastatin induces the recruitment of Tregs via up-regulation of CCR1 in a murine skin delayed-type hypersensitivity model [35]. Besides, CCR2 and CCR4 were also proven in other models to have the capacity to guide Tregs into inflammatory sites [36,37]. 5. Role of Tregs in the onset of MI Rupture or erosion of the destabilized atherosclerotic plaque and subsequent coronary thrombotic occlusion or spasm are the pathologic basis of acute MI [38]. Recent studies have revealed that Tregs contributed to the stability of atherosclerotic lesion. Decreased number of Tregs was shown in human vulnerable atherosclerotic lesions than in stable lesions [39,40]. Expansion of Tregs by using IL-2/anti-IL-2 complex in LDL-receptor knockout (LDL−/−) mice with well-established atherosclerosis showed an increased stability indicated by enhanced collagen content in the lesions [41]. Correspondingly, Xiao Meng and colleagues also discovered a declined disruption rate of the carotid atherosclerotic plaques in a dose-dependent manner after adoptive transfer of Tregs to apolipoprotein E knockout (ApoE−/−) mice. The results showed a significant increase of smooth muscle cells and collagen as well as a substantial decrease of macrophage and lipids content in the lesions [42]. Tregs probably stabilize the atherosclerotic plaques through reducing production of inflammatory cytokines such as tumor necrosis factor (TNF)-α, inhibiting expression of matrix metalloproteinase (MMP)-2 and MMP-9, and enhancing expression of prolyl-4-hydroxylase α1 which determines the maturation and synthesis of collagens. This effect was largely mediated by TGF-β and IL-10 [42]. In addition, Tregs inhibit the migration and adhesion capacity of mature DCs, preventing their recruitment into atherosclerotic lesions and stimulation of effector T cells
[39]. These discoveries indicated a patent therapy to stabilize plaques and thus to prevent the development of acute MI. 6. Role of Tregs in myocardial IRI Myocardial reperfusion therapy is a great milestone in the management of MI. However, reperfusion injury diminishes the full benefits of reperfusion therapy and therefore tempers its further progress [3]. This reperfusion injury contributes to myocardial stunning, no-reflow phenomenon, arrhythmia and cardiomyocyte death [43]. Minimizing IRI is of great significance in improving the efficacy of reperfusion therapies. The pathogenesis of myocardial IRI is multi-factorial, however, it is well established that innate and adaptive immunity plays an essential role in mediating IRI [44,45]. Recently, accumulating evidence has indicated that Tregs do protect multiple organs, such as intestine, liver, kidney etc., from IRI by regulating immune and inflammatory responses [46–48]. Partial depletion of Tregs in mice before ischemiareperfusion by using anti-CD25 monoclonal antibodies (PC61) exacerbated IRI, and further enhanced the accumulation of inflammatory cells such as neutrophils, CD4+ T cells and the production of inflammatory cytokines, including TNF-α and IFN-γ. In contrast, adoptive transfer of Tregs attenuated IRI and alleviated tissue inflammatory state [46,47]. Investigation on the role of Tregs in myocardial IRI is quite limited. As we know, numerous adjuvant therapeutic strategies help to attenuate myocardial IRI, mainly including pharmacological interventions and ischemic conditioning [49]. Recent experimental studies have illustrated an involvement of Tregs in some pharmacological interventions adjuvant to reperfusion treatment. One study [50] demonstrated that pretreatment with rosuvastatin before myocardial ischemiareperfusion attenuated cardiac injury, reduced inflammatory cell infiltration, as well as enhanced the accumulation of Tregs in the heart. Moreover, the number of infiltrated inflammatory cells in myocardium was inversely related to the number of Tregs, suggesting the cardiac
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protection against IRI by rosuvastatin was partially mediated by immunosuppression of Tregs. Pretreatment with FTY720, an analog of sphingosine-1-phosphate, also has a protective effect on mouse myocardial IRI [51]. And it is confirmed that FTY720 has the ability to induce functional activity of Tregs [52]. But whether Tregs play a role in FTY720-mediated cardiac protection against IRI needs further elucidation. In addition, it demands further efforts to investigate whether Tregs are associated with other adjuvant therapies to myocardial reperfusion treatment, such as ischemic conditioning and heat preconditioning. Together, these findings indicated that strategies targeting expanding Tregs in vivo could be promising in attenuating myocardial IRI.
7. Role of Tregs in the repair and remodeling after MI The ischemic heart undergoes a series of compensatory changes in ventricular size, shape and function to maintain sufficient cardiac output required by human body. This pathological process is called ventricular remodeling [53], mainly manifested as ventricular hypertrophy and dilation. Nevertheless, persistent or exaggerated inflammatory reaction during MI enhances degradation of extracellular matrix, increases ardiomyocyte apoptosis, and promotes interstitial fibrosis. Those processes lead to adverse ventricular remodeling, which represents maladaptive repair and is the major mechanism of heart failure [13]. Therefore, restraining excessive inflammation is important in attenuating adverse remodeling and improving cardiac healing after MI. Increasing evidence indicated the involvement of Tregs in cardiac healing process after MI [13,32,54]. Expansion of Tregs in vivo by both adoptive transfer of CD4+ CD25+ Tregs and administration of CD28 super agonistic antibody (JJ316) improves ventricular contractility and attenuates MI-induced remodeling as indicated by reduced interstitial fibrosis, impaired MMP activity and decreased cardiomyocyte apoptosis
[13,54]. In contrast, Treg depletion by PC61 contributes to early postinfarct dilation and increased left ventricular end-diastolic volume [32]. Mechanistically, on the one hand, Tregs inhibit the recruitment of pro-inflammatory cells including neutrophils, monocytes, CD4+ T lymphocytes etc. into post-infarct hearts and suppress the local expression of inflammatory cytokines including TNF-α, IL-1β etc. [54] (see Fig. 2). Tingting Tang also demonstrated that Tregs inhibited the cytotoxicity of CD8+ T lymphocytes to cardiomyocytes in vitro and restrained their proliferation in vivo [54]. It is well established that upon infiltration into inflammatory tissue, monocytes differentiate into two distinct macrophage phenotypes: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages [55]. Johannes Weirather et al. [56] demonstrated that modulating the process of macrophage differentiation by Tregs was probably one of the mechanisms responsible for their protection against adverse remodeling after MI. They found depletion of Tregs before MI by using Foxp3DTR mice or PC61 administration promoted M1-like macrophage polarization, while Treg activation using superagonistic CD28-specific monoclonal antibodies induced M2-like macrophage differentiation (see Fig. 2). On the other hand, Tregs participate in promoting post-infarct cardiac repair also by affecting reparative immune cells involved in MI. Fibroblasts/myofibroblasts play a pivotal role in repair of injured myocardium with the main function of secreting collagen, which is the major component of extracellular matrix (ECM) [57]. However, persistent activation of myofibroblasts promotes fibrosis and adverse ventricular remodeling. Amit Saxena et al. [32] demonstrated that in vitro, Tregs had the ability to modulate the phenotype and function of cardiac fibroblasts. The cardiac fibroblasts co-cultured with Tregs exhibited a reduction of α-smooth muscle actin expression, decreased expression of MMP-3, and marked attenuation of gel contraction, suggesting compromised transdifferentiation of myofibroblasts. In addition, the co-culture system also showed decreased expression of MMPs, which function as degrading ECM. Regulation of the
Fig. 2. Tregs are involved in the repair and remodeling process after myocardial infarction through infecting different types of cells. They can inhibit the recruitment of inflammatory cells (neutrophils, monocytes, CD4+ T lymphocytes etc.) into post-infarct hearts, skew the ratio of macrophage 1/macrophage 2 towards macrophage 2, inhibit the transdifferentiation of fibroblasts into myofibroblasts, and prevent the apoptosis of cardiomyocytes.
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phenotype and function of fibroblasts/myofibroblasts probably makes a contribution to the beneficial effect of Tregs on post-MI remodeling (see Fig. 2). Interestingly, besides affecting immune cells, Tregs may also exert beneficial effect on post-infarct remodeling through direct protection of cardiomyocytes. Tregs protected co-cultured neonatal rat cardiomyocytes from lipopolysaccharide (LPS)-induced apoptosis by IL-10 as well as direct cell–cell contact (see Fig. 2). Tregs also reduced the production of pro-inflammatory cytokines (TNF-α, IL-1β) by cardiomyocytes stimulated by LPS [54]. In conclusion, these findings indicate promising therapeutic value of Tregs in attenuating post-MI remodeling and thus improving the prognosis of patients with MI. However, more detailed mechanisms accounting for how Tregs affect the immune cells and whether interaction between Tregs and other cell types is associated with post-MI remodeling are still not fully understood.
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transfer of Tregs that are capable of trafficking into inflammatory hearts may be more effective. Thus, it still requires further studies to successfully transform expansion of Tregs into a clinical effective therapy for MI. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. Acknowledgment This work was supported by grants from the National Natural Science Foundation of China (No. 81270179 and No. 81470384 to Mei-xiang Xiang).
8. Summary References Tregs, a specific immunosuppressive subset of T cells, has been indicated to have beneficial effect on numerous diseases, including rheumatoid arthritis [58], systemic lupus erythematosus [59], colitis [60] and atherosclerosis [20]. It is firmly established that inflammation and immune responses are crucially involved in MI. Recently, compelling evidence has demonstrated that Tregs also play a protective role in the onset of MI, myocardial IRI and post-infarct remodeling process by inhibiting undesired inflammatory responses. Moreover, smoking is considered one of the main risk factors for developing coronary heart disease, but disappointingly, the introduction of the smoking ban in Malta exhibited no immediate or significant reduction in the admission rate and mortality of ACS [61]. This could be due to lack of proper enforcement of the ban or inadequate awareness regarding the bad effects of smoking. There was one study suggested that the proportions of subpopulations of Tregs were altered in the blood and bronchoalveolar lavage samples of smokers with normal pulmonary function and patients with chronic obstructive pulmonary disease compared with non-smokers [62]. This indicated a possible involvement of Tregs in smoking-related diseases, and Tregs might be a more feasible and effective therapeutic target than smoking ban legislation in these diseases. This arises our great interest to verify whether Tregs play a role in smoking-induced coronary atherosclerosis in the following research. Although numerous studies suggested expansion and activation of Tregs might be a promising new strategy for preventing and treating MI, there are still some essential problems to overcome before clinical application. One problem is the difficulty in identifying Tregs. Different methods of defining Tregs may partially bear responsibility for some conflicting results in different studies, and expression of CD25 and Foxp3 is also found in activated conventional CD4+ T cells [29]. To better understand the function of Tregs, more specific identification should be explored. Another problem is how to expand Tregs in vivo. In brief, there are two ways by which we can increase the number of Tregs: one is to induce the differentiation of Tregs from naive precursors by administrating particular agents; the other is adoptive transfer of Tregs isolated from human peripheral blood and expanded ex vivo [15,21]. Certain kinds of agents, such as IL-2/anti-IL-2 complex, have been reported in animal experiments with the ability to expand Tregs in vivo [63], enabling them to attenuate inflammation-induced injuries [64]. However, their safety and efficacy in human needs further elucidation. In addition, a larger fraction of the injected Tregs was found located in the spleen than in the heart [13]. As reviewed by Jochen Huehn and Alf Hamann [31], migration and localization also influence the suppressive capacity of Tregs: some subsets of Tregs are recruited in lymphoid tissue to suppress the initiation of immune responses, and other subsets enter inflammatory sites to restrain established immune reaction. The different homing preferences are dependent on molecules expressed on the surface of different subsets of Tregs. For MI patients, adoptive
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