Impaired Thymic Export and Increased Apoptosis Account for Regulatory T Cell Defects in Patients with Non-ST Segment Elevation Acute Coronary Syndrome

Zhang, Wencai; Wang, Jun; Shu, Yan-Wen; Tang, Tingting; Zhu, Zhengfeng; Xia, Ni; Nie, Shaofang; Liu, Juan; Zhou, Siyu; Li, Jingjing; Xiao, Hong; Yuan, Jing; Liao, Mengyang; Cheng, Long; Liao, Yuhua; Cheng, Xiang

doi:10.1074/jbc.m112.382978

Cited by 52 publications

(57 citation statements)

References 66 publications

(26 reference statements)

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“…We also found that the gene expression levels of FOXP3 and GARP among patient PBMCs were reduced compared to the control group. Thus, our results support previous findings indicating that circulating CD4 + CD25 + FOXP3 + Tregs are reduced in patients with ACS [8,9,15,26]. …”

Section: Discussionsupporting

confidence: 82%

“…Moreover, this difference was positively correlated with the frequency of CD4 + CD25 + GARP + Tregs, although there was no significant difference in IL-10 levels. These data are similar to those reported in previous studies [26,31] and may be explained by the finding that LAP (a precursor of TGF-β1) forms complexes with GARP; in particular, these complexes are downregulated in ACS [our unpublished data] and may therefore lead to a reduction in the level of TGF-β1.…”

Section: Discussionsupporting

confidence: 80%

“…Regulatory T cells represent a unique type of T cell that can suppress inflammatory responses, counterbalance plaque formation, and play a pivotal role in inhibiting atherosclerosis initiation and progression. Previous studies have demonstrated that CD4 + CD25 + FOXP3 + Tregs are downregulated in patients with coronary artery disease (CAD) [8,9,15,26]. However, few studies have focused on identifying specific markers of activated Tregs in patients with CAD.…”

Section: Discussionmentioning

confidence: 99%

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Impairment of Circulating CD4⁺CD25⁺GARP⁺Regulatory T Cells in Patients with Acute Coronary Syndrome

Meng

Zhang

Zhong

et al. 2014

Cell Physiol Biochem

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Background: Atherosclerosis (AS) is an inflammatory and immune disease. Regulatory T cells (Tregs) suppress the activation of T cells and have been shown to play a protective role during the pathogenesis of AS. However, specific markers for Tregs are lacking. Recently, glycoprotein A repetitions predominant (GARP) was discovered as a specific marker of activated Tregs, and we therefore utilized GARP as a specific surface marker for Tregs in the current study. Methods: To assess whether GARP⁺ Tregs are downregulated in patients with acute coronary syndrome (ACS), we examined CD4⁺CD25⁺GARP⁺ T cell frequencies as well as their associated cytokines and suppressive function. Additionally, we compared GARP expression to that of FOXP3, which may be more sensitive as a marker of activated Tregs in patients with ACS. Results: Patients with ACS demonstrated a significant decrease in circulating CD4⁺CD25⁺GARP⁺ Tregs. Moreover, the suppressive function of Tregs and levels of related cytokines were also impaired in ACS patients compared to those with stable angina (SA) or normal coronary artery (NCA). Additionally, after TCR stimulation, peripheral blood mononuclear cells (PBMCs) from patients with ACS exhibited a decrease in CD4⁺CD25⁺GARP⁺ Tregs. Conclusions: These fnding indicate that circulating CD4⁺CD25⁺GARP⁺ Tregs are impaired in patients withACS. Thus, targeting GARP may promote the protective function of Tregs in ACS.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Impairment of Circulating CD4⁺CD25⁺GARP⁺Regulatory T Cells in Patients with Acute Coronary Syndrome

Meng

Zhang

Zhong

et al. 2014

Cell Physiol Biochem

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“…Immune activation is considered the most significant feature in determining atherosclerotic plaque vulnerability. Specifically, the presence of activated inflammatory cells in plaque may increase vulnerability to and induce the occurrence of acute cardiovascular events, including ACS, through the release of matrix metalloproteinase, cytokines, and other mediators of inflammation [4,5,6,7,8,9]. Although substantial advances in this field have enhanced our understanding of atherosclerosis pathogenesis, the underlying molecular mechanisms have yet to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Expansion of Myeloid-Derived Suppressor Cells in Patients with Acute Coronary Syndrome

Wang

Xiong

Chen

et al. 2015

Cell Physiol Biochem

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Aim: The aim of this study was to explore whether the circulating frequency and function of myeloid-derived suppressor cells (MDSCs) are altered in patients with acute coronary syndrome (ACS). Methods: The frequency of MDSCs in peripheral blood was determined by flow cytometry, and mRNA expression in purified MDSCs was analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR). The suppressive function of MDSCs isolated from different groups was also determined. The plasma levels of certain cytokines were determined using Bio-Plex Pro™ Human Cytokine Assays. Results: The frequency of circulating CD14⁺HLA-DR^-/low MDSCs; arginase-1 (Arg-1) expression; and plasma levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-33 were markedly increased in ACS patients compared to stable angina (SA) or control patients. Furthermore, MDSCs from ACS patients were more potent suppressors of T-cell proliferation and IFN-γ production than those from the SA or control groups at ratios of 1:4 and 1:2; this effect was partially mediated by Arg-1. In addition, the frequency of MDSCs was positively correlated with plasma levels of IL-6, IL-33, and TNF-α. Conclusions: We observed an increased frequency and suppressive function of MDSCs in ACS patients, a result that may provide insights into the mechanisms involved in ACS.

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“…16 Furthermore, Treg cells inhibit leukocyte-mediated myocardial damage and improve healing after MI through activation of M2-like myocardial macrophages and myofibroblast induction. 17 In addition, agedependent decrease of CD31 + T lymphocytes is associated with a progressive increase of CD31 − T lymphocytes and a subset of these cells, that is, CD31 − CD57 + CD28 − terminally differentiated senescent T cells, has been shown to have a detrimental effect on cardiac healing after MI because of enhanced production of inflammatory cytokines, such as interferon-γ and tumor necrosis factor-α.…”

Section: Article See P 99mentioning

confidence: 99%

Bone Good to the Heart

Picozza

Pompilio

Capogrossi

2015

Circulation Research

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Editorial In this issue of Circulation Research, Shutt et al 1 explore the characteristics of resident bone marrow cells (BMC) in patients enrolled in the Timing In Myocardial infarction Evaluation (TIME) clinical trial, in search of cellular correlates of reduction of the infarcted area 6 months after acute myocardial infarction (MI). The central hypothesis is that endogenous BM properties could affect the clinical outcome. They found both phenotypic and biological BMC correlates of infarct size reduction, and the emerging picture is quite interesting. Article, see p 99Why should subset composition and functional status of BMC affect recovery after acute MI? One explanation relates to the fact that specific populations of BMC have been shown to mobilize from the BM into the peripheral blood (PB) after MI and to have prognostic and therapeutic values. The first clue of a cross talk between the human ischemic heart and the BM came more than a decade ago with the work of Shintani et al, 2 which reported a peak in BM-derived, circulating CD34 + cells 7 days after MI, a trend that correlated with the rise in the number of putative endothelial cell clusters under in vitro angiogenic conditions (ie, in medium supplemented with endothelial cell growth factors). Mobilization of precursor cells after MI was confirmed by subsequent studies: Wojakowski et al 3 showed that, immediately after admission, blood mononuclear cells of patients with ST-segment-elevation myocardial infarction are enriched in transcripts for early myocardial, muscle, and endothelial markers; Leone et al 4 properly. Subsequently, enhanced mobilization of CD34 + hematopoietic stem cell cells in MI was confirmed, and these cells were shown to express the receptor for stromal-derived factor-1, CXCR4, and the adhesion molecule very late antigen-4; expression of these proteins, without being unique, is characteristic of hematopoietic stem cells and probably instrumental in the recruitment of these regenerative populations into the infarcted myocardium.7 Of note, the blockade of both stromal-derived factor-1/CXCR4 axes and very late antigen-4 through the chemical reversible inhibitor AMD3100 and the humanized monoclonal antibody Natalizumab, respectively, results in enhanced mobilization of CD34 + cells from the BM. Furthermore, enhanced levels of circulating CD34 + CXCR4 + precursor cells, accompanied by increased levels of plasmatic G-CSF but reduced stromal-derived factor-1, was recently found to correlate with recovery of left ventricular ejection fraction in patients with MI. 8Despite these previous studies on circulating BMC in acute MI, a detailed evaluation of resident BMC in humans with MI was missing. The work by Shutt et al 1 analyzes the cells in the BM of patients with acute MI for their ability to give rise to endothelial, mesenchymal, and proangiogenic cell colonies, assessed in vitro by endothelial colony-forming cells, colonyforming units (CFU)-fibroblasts, and CFU-Hill assays as surrogate markers of the healing potential of regenerative ...

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Impaired Thymic Export and Increased Apoptosis Account for Regulatory T Cell Defects in Patients with Non-ST Segment Elevation Acute Coronary Syndrome

Cited by 52 publications

References 66 publications

Impairment of Circulating CD4⁺CD25⁺GARP⁺Regulatory T Cells in Patients with Acute Coronary Syndrome

Impairment of Circulating CD4⁺CD25⁺GARP⁺Regulatory T Cells in Patients with Acute Coronary Syndrome

Expansion of Myeloid-Derived Suppressor Cells in Patients with Acute Coronary Syndrome

Bone Good to the Heart

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Impaired Thymic Export and Increased Apoptosis Account for Regulatory T Cell Defects in Patients with Non-ST Segment Elevation Acute Coronary Syndrome

Cited by 52 publications

References 66 publications

Impairment of Circulating CD4+CD25+GARP+Regulatory T Cells in Patients with Acute Coronary Syndrome

Impairment of Circulating CD4+CD25+GARP+Regulatory T Cells in Patients with Acute Coronary Syndrome

Expansion of Myeloid-Derived Suppressor Cells in Patients with Acute Coronary Syndrome

Bone Good to the Heart

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Product

Resources

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Impairment of Circulating CD4⁺CD25⁺GARP⁺Regulatory T Cells in Patients with Acute Coronary Syndrome

Impairment of Circulating CD4⁺CD25⁺GARP⁺Regulatory T Cells in Patients with Acute Coronary Syndrome