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1.  Dysregulated balance of Th17 and Th1 cells in systemic lupus erythematosus 
Introduction
Interleukin (IL)-17 is a proinflammatory cytokine that is produced largely by a unique CD4+ T-helper (Th) subset called Th17 cells. The development of Th17 cells is suppressed by interferon (IFN)-γ produced by Th1 cells, suggesting cross-regulation between Th17 and Th1 cells. Thus, this study analyzed the balance of CD4+ Th17 and Th1 cell responses in peripheral blood from patients with systemic lupus erythematosus (SLE) and healthy subjects.
Methods
Twenty-five adult patients with SLE and 26 healthy subjects matched for gender and age (± 2 years) were recruited. Peripheral blood mononuclear cells (PBMCs) from patients and healthy subjects were stimulated for 4 h ex vivo with phorbol myristate acetate (PMA) and ionomycin. The frequency of CD4+ T cells producing IL-17 and/or IFN-γ was measured by using flow cytometry. Expression of Th17-associated chemokine receptors CCR4 and CCR6 on CD4+ T cells as well as plasma levels of Th17-polarizing cytokines were assessed. Disease activity was evaluated by the SLE disease activity index score (SLEDAI). Unpaired t test and Pearson correlation were used for statistical analyses.
Results
Patients with SLE had an increased frequency of CD4+IL-17+ T cells compared with healthy subjects. However, the frequency of CD4+IFN-γ+ T cells was similar between the two groups, indicating an altered balance of Th17 and Th1 cell responses in SLE. Patients with SLE also had an increased frequency of CD4+CCR4+CCR6+ T cells that are known to produce IL-17. The frequency of CD4+IL-17+ T cells and CD4+CCR4+CCR6+ T cells correlated with disease activity. In measuring plasma levels of the Th17-polarizing cytokines, levels of IL-6 were higher in patients with SLE than in healthy subjects, although levels of IL-1β, IL-21, IL-23, and transforming growth factor (TGF)-β were not different between the two groups.
Conclusions
We demonstrate an enhanced Th17 cell response that correlates with disease activity in patients with SLE, suggesting a role for IL-17 in the pathogenesis of lupus. Our data indicate that the mechanisms involved in balancing Th1 and Th17 regulation, as well as in producing IL-6, are aberrant in SLE, leading to an increased Th17 response. We suggest that CCR4 and CCR6 expression on CD4+ T cells should be considered as markers of disease activity, and that IL-17 blocking may offer a therapeutic target in SLE.
doi:10.1186/ar2964
PMCID: PMC2888202  PMID: 20334681
2.  Impaired Coronary Flow Reserve Is the Most Important Marker of Viable Myocardium in the Myocardial Segment-Based Analysis of Dual-Isotope Gated Myocardial Perfusion Single-Photon Emission Computed Tomography 
Korean Journal of Radiology  2014;15(2):277-285.
Objective
The aim of this study was to investigate the most robust predictor of myocardial viability among stress/rest reversibility (coronary flow reserve [CFR] impairment), 201Tl perfusion status at rest, 201Tl 24 hours redistribution and systolic wall thickening of 99mTc-methoxyisobutylisonitrile using a dual isotope gated myocardial perfusion single-photon emission computed tomography (SPECT) in patients with coronary artery disease (CAD) who were re-vascularized with a coronary artery bypass graft (CABG) surgery.
Materials and Methods
A total of 39 patients with CAD was enrolled (34 men and 5 women), aged between 36 and 72 years (mean 58 ± 8 standard in years) who underwent both pre- and 3 months post-CABG myocardial SPECT. We analyzed 17 myocardial segments per patient. Perfusion status and wall motion were semi-quantitatively evaluated using a 4-point grading system. Viable myocardium was defined as dysfunctional myocardium which showed wall motion improvement after CABG.
Results
The left ventricular ejection fraction (LVEF) significantly increased from 37.8 ± 9.0% to 45.5 ± 12.3% (p < 0.001) in 22 patients who had a pre-CABG LVEF lower than 50%. Among 590 myocardial segments in the re-vascularized area, 115 showed abnormal wall motion before CABG and 73.9% (85 of 115) had wall motion improvement after CABG. In the univariate analysis (n = 115 segments), stress/rest reversibility (p < 0.001) and 201Tl rest perfusion status (p = 0.024) were significant predictors of wall motion improvement. However, in multiple logistic regression analysis, stress/rest reversibility alone was a significant predictor for post-CABG wall motion improvement (p < 0.001).
Conclusion
Stress/rest reversibility (impaired CFR) during dual-isotope gated myocardial perfusion SPECT was the single most important predictor of wall motion improvement after CABG.
doi:10.3348/kjr.2014.15.2.277
PMCID: PMC3955796  PMID: 24642696
Myocardium; Tissue viability; Ischemia; Coronary artery bypass grafting; Single-photon emission-computed tomography
3.  Maintenance of CMV-specific CD8+ T cell responses and the relationship of IL-27 to IFN-γ levels with aging 
Cytokine  2012;61(2):485-490.
We investigated whether healthy young (age ≤ 40) and elderly (age ≥ 65) people infected with cytomegalovirus (CMV) had similar levels of CD8+ T cell cytokine production and proliferation in response to an immunodominant CMV pp65 peptide pool given the role of CD8+ T cells in controlling viral infection and the association of CMV with immunosenescence. Plus, we determined the effects of aging and CMV-infectious status on plasma levels of IL-27, an innate immune cytokine with pro- and anti-inflammatory properties, as well as on its relationship to IFN-γ in that IL-27 can promote the production of IFN-γ. The results of our study show that young and elderly people had similar levels of CD8+ T cell proliferation, and IFN-γ and TNF-α production in response to CMV pp65 peptides. Plasma levels of IL-27 were similar between the two groups although CMV-infected young and elderly people had a trend toward increased levels of IL-27. Regardless of aging and CMV-infectious status, plasma levels of IL-27 correlated highly with plasma levels of IFN-γ. These findings suggest the maintenance of CMV pp65-specific CD8+ T cell proliferation and cytokine production with aging as well as the sustaining of circulatory IL-27 levels and its biological link to IFN-γ in young and elderly people irrespective of CMV infection.
doi:10.1016/j.cyto.2012.11.024
PMCID: PMC3563774  PMID: 23280240
CD8+ T cells; IL-27; Human; aging; cytomegalovirus (CMV)
4.  Improved measurement of the glomerular filtration rate from Tc-99m DTPA scintigraphy in patients following nephrectomy 
European Radiology  2013;24:413-422.
Objective
We aimed to improve Tc-99m DTPA glomerular filtration rate (GFR) scintigraphy (Gates’ method) in a prospective study using Cr-51 EDTA GFR test as a gold standard.
Methods
Fifty-seven Tc-99m DTPA GFR scintigrams in 45 subjects (male/female = 33:12, age = 45.9 ± 17.6 years, 14 healthy volunteers and 31 nephrectomised patients) were compared using Cr-51 EDTA GFR tests. Using the %renal uptake of Tc-99m DTPA and Cr-51 EDTA GFR, a revised equation for GFR was established through linear regression analysis.
Results
The revised equation for improved GFR was GFR(mL/min) = (%renal uptake × 11.7773) − 0.7354. Gates’ original GFRs (70.1 ± 20.5 mL/min/1.73 m2) were significantly lower than Cr-51 EDTA GFRs (97.0 ± 31.9 mL/min/1.73 m2; P < 0.0001), but the improved GFRs (98.0 ± 26.3 mL/min/1.73 m2) were not different from (P = 0.7360) and had a significant correlation with (r = 0.73, P < 0.0001) the Cr-51 EDTA GFRs. The revised GFR equation effectively demonstrated perioperative GFR changes in kidneys that were operated on and the contralateral kidneys at 3 and 6 months post-partial nephrectomy (n = 25).
Conclusions
GFR measurement using Tc-99m DTPA scintigraphy could be significantly improved by a revised equation derived from the comparison with Cr-51 EDTA GFR.
Key Points
• Measurement of glomerular filtration rate is difficult following nephrectomy.
• Measurements can be significantly improved by new renal sctintigraphic methods.
• This helps physicians to measure kidney function of patients following nephrectomy.
• Management of renal tumour patients should become more effective.
doi:10.1007/s00330-013-3039-z
PMCID: PMC3890538  PMID: 24141715
Gamma camera imaging; Glomerular filtration rate; Tc-99m DTPA; Nephrectomy; Cr-51 EDTA
5.  Stem cell membrane engineering for cell rolling using peptide conjugation and tuning of cell-selectin interaction kinetics 
Biomaterials  2012;33(20):5004-5012.
Dynamic cell-microenvironment interactions regulate many biological events and play a critical role in tissue regeneration. Cell homing to targeted tissues requires well balanced interactions between cells and adhesion molecules on blood vessel walls. However, many stem cells lack affinity with adhesion molecules. It is challenging and clinically important to engineer these stem cells to modulate their dynamic interactions with blood vessels. In this study, a new chemical strategy was developed to engineer cell-microenvironment interactions. This method allowed the conjugation of peptides onto stem cell membranes without affecting cell viability, proliferation or multipotency. Mesenchymal stem cells (MSCs) engineered in this manner showed controlled firm adhesion and rolling on E-selectin under physiological shear stresses. For the first time, these biomechanical responses were achieved by tuning the binding kinetics of the peptide-selectin interaction. Rolling of engineered MSCs on E-selectin is mediated by a Ca2+ independent interaction, a mechanism that differs from the Ca2+ dependent physiological process. This further illustrates the ability of this approach to manipulate cell-microenvironment interactions, in particular for the application of delivering cells to targeted tissues. It also provides a new platform to engineer cells with multiple functionalities.
doi:10.1016/j.biomaterials.2012.03.065
PMCID: PMC3366278  PMID: 22494889
6.  The Relationship of Cytomegalovirus (CMV) Infection with circulatory IFN-α levels and IL-7 receptor α expression on CD8+ T cells in Human Aging 
Cytokine  2012;58(3):332-335.
The IL-7 receptor alpha (IL-7Rα) is the high affinity receptor for IL-7 which is essential for T cell homeostasis. We recently reported an age-associated expansion of human effector memory (EM) CD8+ T cells expressing IL-7Rα low (IL-7Rαlow), which could be detrimental to hosts by occupying “immunological space”. We investigated the potential mechanisms for this phenomenon, focusing on cytomegalovirus (CMV) infection and INF-α. In the elderly (age≥65), CMV infection was associated with a decreased frequency of naïve CD8+ T cells as well as with an increased frequency of total EM and IL-7Rαlow EM CD8+ T cells. However, in the young (age≤40), this viral infection was associated only with an increased frequency of IL-7Rαlow EM CD8+ T cells. There was no association found between CMV immune status and plasma levels of IFN-α. In CMV-infected young and elderly people, INF-α levels had no correlation with the frequency of IL-7Rαlow EM CD8+ T cells although this cytokine levels correlated with the frequency of IL-7Rαlow CD45RA+ EM CD8+ T cells in CMV-uninfected elderly people. Our findings suggest that the effect of CMV infection on the frequency of CD8+ T cell subsets may begin with IL-7Rαlow EM CD8+ T cells and spread to other subsets with aging. Also, IFN-α could be associated with the expansion of IL-7Rαlow CD45RA+ EM CD8+ T cells in the CMV-uninfected elderly.
doi:10.1016/j.cyto.2012.03.013
PMCID: PMC3340433  PMID: 22484243
Human; aging; cytomegalovirus (CMV); IL-7; CD8+ T cells
7.  1,25(OH)2 vitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved non-coding sequence region 
Forkhead box P3 (FOXP3)-positive regulatory T cells (Treg) are a unique subset of T cells with immune regulatory properties. Treg cells can be induced from non-Treg CD4+ T cells (induced Treg, iTreg) by T cell receptor (TCR) triggering, IL-2 and TGF-β or retinoic acid. 1,25(OH)2 vitamin D3 (VD3) affects the functions of immune cells including T cells. 1,25(OH)2VD3 binds the nuclear vitamin D receptor (VDR) that binds target DNA sequences known as the vitamin D response element (VDRE). Although 1,25(OH)2VD3 can promote FOXP3 expression in CD4+ T cells with TCR triggering and IL-2, it is unknown whether this effect of 1,25(OH)2VD3 is mediated through direct binding of VDR to the FOXP3 gene without involving other molecules. Also, it is unclear whether FOXP3 expression in 1,25(OH)2VD3-induced Treg (VD-iTreg) cells is critical for the inhibitory function of these cells. Here we demonstrated the presence of VDREs in the intronic conserved non-coding sequence (CNS) region +1714 to +2554 of the human FOXP3 gene and the enhancement of the FOXP3 promoter activity by such VDREs in response to 1,25(OH)2VD3. In addition, VD-iTreg cells suppressed the proliferation of target CD4+ T cells and this activity was dependent on FOXP3 expression. These findings suggest that 1,25(OH)2VD3 can affect human immune responses by regulating FOXP3 expression in CD4+ T cells through direct VDR binding to the FOXP3 gene which is essential for inhibitory function of VD-iTreg cells.
doi:10.4049/jimmunol.1101211
PMCID: PMC3358577  PMID: 22529297
8.  Bone Positron Emission Tomography with or without CT Is More Accurate than Bone Scan for Detection of Bone Metastasis 
Korean Journal of Radiology  2013;14(3):510-519.
Objective
Na18F bone positron emission tomography (bone PET) is a new imaging modality which is useful for the evaluation of bone diseases. Here, we compared the diagnostic accuracies between bone PET and bone scan for the detection of bone metastasis (BM).
Materials and Methods
Sixteen cancer patients (M:F = 10:6, mean age = 60 ± 12 years) who underwent both bone PET and bone scan were analyzed. Bone PET was conducted 30 minutes after the injection of 370 MBq Na18F, and a bone scan was performed 3 hours after the injection of 1295 MBq 99mTc-hydroxymethylene diphosphonate.
Results
In the patient-based analysis (8 patients with BM and 8 without BM), the sensitivities of bone PET (100% = 8/8) and bone scan (87.5% = 7/8) were not significantly different (p > 0.05), whereas the specificity of bone PET (87.5% = 7/8) was significantly greater than that of the bone scan (25% = 2/8) (p < 0.05). In the lesion-based analysis (43 lesions in 14 patients; 31 malignant and 12 benign), the sensitivity of bone PET (100% = 31/31) was significantly greater than that of bone scan (38.7% = 12/31) (p < 0.01), and the specificity of bone PET (75.0% = 9/12) was also significantly higher than that of bone scan (8.3% = 1/12) (p < 0.05). The receiver operating characteristic curve analysis showed that bone PET was significantly more accurate than the bone scan in the patient (p = 0.0306) and lesion (p = 0.0001) based analyses.
Conclusion
Na18F bone PET is more accurate than bone scan for BM evaluation.
doi:10.3348/kjr.2013.14.3.510
PMCID: PMC3655309  PMID: 23690722
Na18F; Positron emission tomography; Positron emission tomography/computed tomography; 99mTc-HDP; Bone scan; Bone metastasis
9.  Active Hexose Correlated Compound promotes T helper (Th) 17 and 1 cell responses via inducing IL-1β production from monocytes in humans. 
Cellular Immunology  2012;275(1-2):19-23.
The differentiation of T helper (Th) cells is critically dependent on cytokine milieu. The innate immune monocytes produce IL-1β which can affect the development of Th17 and Th1 cells that predominantly produce IL-17 and IFN-γ, respectively. Oligosaccharides from microorganisms, crops and mushrooms can stimulate innate immune cells. Active Hexose Correlated Compound (AHCC) that contains a large amount of oligosaccharides is a natural extract prepared from the mycelium of the edible Basidiomycete fungus. This compound is reported to modulate immune responses against pathogens although the mechanisms for this effect are largely unknown. Here we show that AHCC could induce high levels of IL-1β production from human monocytes. Furthermore, AHCC-treated monocytes increased the production of IL-17 and IFN-γ from autologous CD4+ T cells, which was blocked by adding IL-1 receptor antagonist. These finding provide new insight into how food supplements like AHCC could enhance human immunity by modulating monocytes and Th cells.
doi:10.1016/j.cellimm.2012.04.001
PMCID: PMC3348379  PMID: 22531483
Cytokines; T helper cells; monocytes
10.  Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity 
Nature medicine  2012;18(10):1518-1524.
The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced ERK phosphorylation in naïve CD4+ T cells (P<0.0001) while other signals, such as ZAP70 and PLC-γ1 phosphorylation were not impaired. The defective ERK signaling was caused by the dual specific phosphatase (DUSP) 6 whose protein levels increased with age (r = 0.68, P < 0.0001) due to a decline in repression by miR-181a (r = −0.59, P < 0.0001). Reconstitution of miR-181a lowered DUSP6 levels in naïve CD4+ T cells in elderly individuals. DUSP6 repression with miR-181a or specific siRNA, and DUSP6 inhibition with the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4+ T cell responses as seen by increased expression of activation markers, improved proliferation and supported preferential TH1 differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.
doi:10.1038/nm.2963
PMCID: PMC3466346  PMID: 23023500
11.  Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis 
IL-1b signaling augments continued splenic monocyte supply during acute inflammation.
Monocytes (Mo) and macrophages (MΦ) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/MΦ and their effector functions without compromising innate immunity’s critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/MΦ in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1β; and e) the balance of cell recruitment and local death shifted during resolution of inflammation. Depending on the experimental approach, we measured a 24 h Mo/MΦ exit rate from infarct tissue between 5 and 13% of the tissue cell population. Exited cells were most numerous in the blood, liver, and spleen. Abrogation of extramedullary monocytopoiesis proved deleterious for infarct healing and accelerated the evolution of heart failure. We also detected rapid Mo kinetics in mice with stroke. These findings expand our knowledge of Mo/MΦ flux in acute inflammation and provide the groundwork for novel anti-inflammatory strategies for treating heart failure.
doi:10.1084/jem.20111009
PMCID: PMC3260875  PMID: 22213805
12.  Age-associated alteration in naive and memory Th17 cell response in humans 
Th17 cells produce IL-17 that plays an important role in host defense. However, little is known about whether aging affects human Th17 cells. Here we demonstrated that healthy elderly people (age≥65) had a decreased frequency of IL-17-producing cells in memory CD4+ T cells compared to healthy young people (age≤40) while both groups had similar frequencies of IFN-γ-producing cells in the same memory cell subset as measured by flow cytometry. In contrast, the healthy elderly had increased differentiation of IL-17-producing effector cells but not IFN-γ-producing cells from naïve CD4+ T cells compared to the healthy young. The results of ELISA also showed similar findings with increased IL-17 production from naïve CD4+ T cells and decreased IL-17 production from memory CD4+ T cells in the elderly compared to the young. These findings indicate that aging differentially affects naïve and memory Th17 cell responses in humans.
doi:10.1016/j.clim.2011.03.018
PMCID: PMC3115516  PMID: 21489886
Human; aging; IL-17; T helper 17 (Th17) cells; CD4+ T cells
13.  Antibacterial effect of citrus press-cakes dried by high speed and far-infrared radiation drying methods 
Nutrition Research and Practice  2012;6(3):187-194.
In this study, the antibacterial effect was evaluated to determine the benefits of high speed drying (HSD) and far-infrared radiation drying (FIR) compared to the freeze drying (FD) method. Citrus press-cakes (CPCs) are released as a by-product in the citrus processing industry. Previous studies have shown that the HSD and FIR drying methods are much more economical for drying time and mass drying than those of FD, even though FD is the most qualified drying method. The disk diffusion assay was conducted, and the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined with methanol extracts of the dried CPCs against 11 fish and five food-related pathogenic bacteria. The disk diffusion results indicated that the CPCs dried by HSD, FIR, and FD prevented growth of all tested bacteria almost identically. The MIC and MBC results showed a range from 0.5-8.0 mg/mL and 1.0-16.0 mg/mL respectively. Scanning electron microscopy indicated that the extracts changed the morphology of the bacteria cell wall, leading to destruction. These results suggest that CPCs dried by HSD and FIR showed strong antibacterial activity against pathogenic bacteria and are more useful drying methods than that of the classic FD method in CPCs utilization.
doi:10.4162/nrp.2012.6.3.187
PMCID: PMC3395782  PMID: 22808341
Citrus press-cakes; fish and food-related pathogenic bacteria; high speed drying; far-infrared radiation drying; antibacterial agent
14.  Therapeutic siRNA silencing in inflammatory monocytes 
Nature Biotechnology  2011;29(11):1005-1010.
Inflammatory monocytes -- but not the non-inflammatory subset -- depend on the chemokine receptor CCR2 for distribution to injured tissue and stimulate disease progression. Precise therapeutic targeting of this inflammatory monocyte subset could spare innate immunity's essential functions for maintenance of homeostasis and thus limit unwanted effects. Here we developed siRNA nanoparticles targeting CCR2 expression in inflammatory monocytes. We identified an optimized lipid nanoparticle and silencing siRNA sequence that when administered systemically, had rapid blood clearance, accumulated in spleen and bone marrow and showed high cellular localization of fluorescently tagged siRNA inside monocytes. Efficient degradation of CCR2 mRNA in monocytes prevented their accumulation in sites of inflammation. Specifically, the treatment attenuated their number in atherosclerotic plaques, reduced infarct size following coronary artery occlusion, prolonged normoglycemia in diabetic mice after pancreatic islet transplantation and resulted in reduced tumor volumes and lower numbers of tumor-associated macrophages. Taken together, siRNA nanoparticle-mediated CCR2 gene silencing in leukocytes selectively modulates functions of innate immune cell subtypes and may allow for the development of specific anti-inflammatory therapy.
doi:10.1038/nbt.1989
PMCID: PMC3212614  PMID: 21983520
15.  PET/MRI of inflammation in myocardial infarction 
Objectives
The aim of this study was to explore post-MI myocardial inflammation.
Background
Innate immune cells are centrally involved in infarct healing and are emerging therapeutic targets in cardiovascular disease, however; clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the non-ischemic remote zone recruits monocytes.
Methods
Acute inflammation was followed in mice with coronary ligation by 18FDG PET/MRI, FACS, PCR and histology.
Results
Gd-DTPA enhanced infarcts showed high 18FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b+ cells had 4-fold higher 18FDG uptake than the infarct tissue from which they were isolated (P<0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (~104/mg myocardium, 5.6-fold increase, P<0.01), a finding mirrored by macrophage infiltration in remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative PCR showed robust increase of recruiting adhesion molecules and chemokines in remote myocardium (e.g. 12-fold increase of MCP-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in non-infarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post MI dilation.
Conclusion
These studies shed light on the innate inflammatory response in remote myocardium after myocardial infarction.
doi:10.1016/j.jacc.2011.08.066
PMCID: PMC3257823  PMID: 22222080
PET/MRI; myocardial infarction; inflammation; remote myocardium
16.  Regulation of T cell receptor signaling by activation-induced zinc influx 
Zinc enhances TCR signaling in part by inhibiting Shp-1 recruitment to the TCR synapse.
Zinc is a trace element that is essential for innate and adaptive immune responses. In addition to being a structural element of many proteins, zinc also functions as a neurotransmitter and an intracellular messenger. Temporal or spatial changes in bioavailable zinc may influence the activity of several enzymes, including kinases and phosphatases. We provide evidence that zinc functions as an ionic signaling molecule after T cell activation. Cytoplasmic zinc concentrations increased within 1 min after T cell receptor (TCR) triggering, in particular in the subsynaptic compartment. The increase depended on the extracellular zinc concentrations and was inhibited by silencing zinc transporter Zip6. Increased zinc influx reduced the recruitment of SHP-1 to the TCR activation complex, augmented ZAP70 phosphorylation and sustained calcium influx. By calibrating TCR activation thresholds, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli.
doi:10.1084/jem.20100031
PMCID: PMC3135340  PMID: 21422171
17.  ACE inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction 
Circulation research  2010;107(11):1364-1373.
Rationale
Monocytes recruited to ischemic myocardium originate from a reservoir in the spleen, and the release from their splenic niche relies on angiotensin-II (Ang-II) signaling.
Objective
Since monocytes are centrally involved in tissue repair after ischemia, we here hypothesized that early ACE inhibitor therapy impacts healing after myocardial infarction partly via effects on monocyte traffic.
Methods and Results
In a mouse model of permanent coronary ligation, Enalapril arrested the release of monocytes from the splenic reservoir and consequently reduced their recruitment into the healing infarct by 45%, as quantified by flow cytometry of digested infarcts. Time-lapse intravital microscopy revealed that Enalapril reduces monocyte motility in the spleen. In vitro migration assays and Western blotting showed that this was caused by reduced signaling through the Ang-II receptor subtype 1. We then studied the long-term consequences of blocked splenic monocyte release in atherosclerotic apoE-/- mice, in which infarct healing is impaired due to excessive inflammation in the cardiac wound. Enalapril improved histological healing biomarkers and reduced inflammation in infarcts measured by fluorescence molecular tomography (FMT-CT) of proteolytic activity. ACE inhibition improved MRI-derived ejection fraction by 14% on day 21, despite initially comparable infarct size. In apoE-/- mice, ischemia reperfusion injury resulted in larger infarct size, enhanced monocyte recruitment and was reversible by Enalapril treatment. Splenectomy reproduced anti-inflammatory effects of Enalapril.
Conclusion
This study suggests that benefits of early ACE inhibition after MI can partially be attributed to its potent anti-inflammatory impact on the splenic monocyte reservoir.
doi:10.1161/CIRCRESAHA.110.227454
PMCID: PMC2992104  PMID: 20930148
Monocyte; spleen; ACE inhibitor; myocardial infarction; heart failure; wound healing
19.  Age-Dependent Signature of Metallothionein Expression in Primary CD4 T Cell Responses Is Due to Sustained Zinc Signaling 
Rejuvenation research  2008;11(6):1001-1011.
The ability to mount adaptive immune responses to vaccinations and viral infections declines with increasing age. To identify mechanisms leading to immunosenescence, primary CD4 T cell responses were examined in 60- to 75-year-old individuals lacking overt functional defects. Transcriptome analysis indicated a selective defect in zinc homeostasis. CD4 T cell activation was associated with zinc influx via the zinc transporter Zip6, leading to increased free cytoplasmic zinc and activation of negative feedback loops, including the induction of zinc-binding metallothioneins. In young adults, activation-induced cytoplasmic zinc concentrations declined after 2 days to below prestimulation levels. In contrast, activated naïve CD4 T cells from older individuals failed to downregulate cytoplasmic zinc, resulting in excessive induction of metallothioneins. Activation-induced metallothioneins regulated the redox state in activated T cells and accounted for an increased proliferation of old CD4 T cells, suggesting that regulation of T cell zinc homeostasis functions as a compensatory mechanism to preserve the replicative potential of naïve CD4 T cells with age.
doi:10.1089/rej.2008.0747
PMCID: PMC2848531  PMID: 19072254
20.  Unchecked CD70 expression on T cells lowers threshold for T-cell activation in rheumatoid arthritis1 
Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4+CD28− and CD4+CD28+ T cells to discover disease-promoting activities of CD28− T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared to age-matched controls (P<0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4+CD28− T cells functioned by lowering the threshold for T-cell activation; admixture of CD4+CD28− T cells augmented TCR-induced responses of autologous naïve CD4+CD28+ T cells, particularly of low avidity T cells. The data support a model where CD70 expressed on T cells causes degeneracy in T-cell responses and undermines tolerance mechanisms that normally control T-cell autoreactivity.
PMCID: PMC2832914  PMID: 17675524
T cells; Rheumatoid Arthritis; Costimulation; Gene Regulation; Tolerance/Suppression/Anergy
21.  Age-Dependent Signature of Metallothionein Expression in Primary CD4 T Cell Responses Is Due to Sustained Zinc Signaling 
Rejuvenation Research  2008;11(6):1001-1011.
Abstract
The ability to mount adaptive immune responses to vaccinations and viral infections declines with increasing age. To identify mechanisms leading to immunosenescence, primary CD4 T cell responses were examined in 60- to 75-year-old individuals lacking overt functional defects. Transcriptome analysis indicated a selective defect in zinc homeostasis. CD4 T cell activation was associated with zinc influx via the zinc transporter Zip6, leading to increased free cytoplasmic zinc and activation of negative feedback loops, including the induction of zinc-binding metallothioneins. In young adults, activation-induced cytoplasmic zinc concentrations declined after 2 days to below prestimulation levels. In contrast, activated naïve CD4 T cells from older individuals failed to downregulate cytoplasmic zinc, resulting in excessive induction of metallothioneins. Activation-induced metallothioneins regulated the redox state in activated T cells and accounted for an increased proliferation of old CD4 T cells, suggesting that regulation of T cell zinc homeostasis functions as a compensatory mechanism to preserve the replicative potential of naïve CD4 T cells with age.
doi:10.1089/rej.2008.0747
PMCID: PMC2848531  PMID: 19072254
22.  Aging and T-cell diversity 
Experimental gerontology  2007;42(5):400-406.
Naïve and memory CD4 and CD8 T cells represent a highly dynamic system with constant homeostatic and antigen-driven proliferation, influx, and loss of T cells. Thymic activity dwindles with age and essentially ceases in the later decades of life, severely constraining the generation of new T cells. Homeostatic control mechanisms are very effective to maintain a large and diverse subset of naïve CD4 T cells for many years up to the 8th decade of life, but eventually and abruptly fail at about the age of 75 years. In contrast, the CD8 T cell compartment is more unstable, with progressive diminution of naïve T cells and increasing loss of diversity already during mid adulthood. Vaccination strategies need to aim at developing a broad repertoire of memory T cells before the critical time period when the naïve CD4 T-cell repertoire collapses. Research efforts need to aim at understanding the homeostatic control mechanisms to ultimately expand the time period of repertoire stability.
doi:10.1016/j.exger.2006.11.016
PMCID: PMC2680153  PMID: 17218073
23.  T cell subset-specific susceptibility to aging 
Clinical immunology (Orlando, Fla.)  2008;127(1):107-118.
With increasing age, the competence of the immune system to fight infections and tumors declines. Age-dependent changes have been mostly described for human CD8 T cells, raising the question of whether the response patterns for CD4 T cells are different. Gene expression arrays of memory CD4 T cells yielded a similar age-induced fingerprint as has been described for CD8 T cells. In cross-sectional studies, the phenotypic changes were not qualitatively different for CD4 and CD8 T cells, but occurred much more frequently in CD8 T cells. Homeostatic stability partially explained this lesser age sensitivity of CD4 T cells. With aging, naïve and central memory CD8 T cells were lost at the expense of phenotypically distinct CD8 effector T cells, while effector CD4 T cells did not accumulate. However, phenotypic shifts on central memory T cells were also more pronounced in CD8 T cells. This distinct stability in cell surface marker expression can be reproduced in vitro. The data show that CD8 T cells are age sensitive by at least two partially independent mechanisms: fragile homeostatic control and gene expression instability in a large set of regulatory cell surface molecules.
doi:10.1016/j.clim.2007.12.002
PMCID: PMC2435295  PMID: 18222733
immunosenescence; aging; T-cell subset; T-cell homeostasis; CD4; CD8; killer immunoglobulin-like receptors; CD85

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