CD4+T-bet+, CD4+pSTAT3+ and CD8+T-bet+ T cells accumulate in peripheral blood during NZB treatment

2010 ◽  
Vol 17 (5) ◽  
pp. 556-566 ◽  
Author(s):  
Giovanni Frisullo ◽  
Raffaele Iorio ◽  
Domenico Plantone ◽  
Alessandro Marti ◽  
Viviana Nociti ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Relapsing Remitting ◽  
Before And After ◽  
Circulating T Cells ◽  
Relapsing Remitting Multiple Sclerosis

Circulating T cells and monocytes expressing T-bet, pSTAT1 and pSTAT3 increase in relapsing–remitting multiple sclerosis (RRMS) during relapse. Natalizumab (NZB) is an effective drug in RRMS, but exacerbation of the disease after its discontinuation has been described in some patients. The aim of this research was to study the effect of NZB treatment on circulating lymphomonocyte subpopulations expressing T-bet, pSTAT1, pSTAT3 and CD4+CD25+Foxp3+ regulatory T cells. Flow cytometry was used to evaluate the percentages of circulating CD4+ and CD8+ T cells, CD14+ monocytes and B cells expressing T-bet, pSTAT1, and pSTAT3, and CD4+CD25+Foxp3+ regulatory T cells from RRMS patients before and after 6–12 NZB infusions. In NZB-treated RRMS patients, the percentages of CD4+pSTAT1+ and CD8+pSTAT1+ T cells, CD14+pSTAT1+ monocytes, CD4+T-bet+, CD8+T-bet+ and CD4+pSTAT3+ T cells and CD14+pSTAT3+ monocytes increased after 12 drug infusions and were similar to those observed in untreated relapsing RRMS patients. Otherwise in vitro NZB exposure of peripheral blood mononuclear cells from untreated RRMS patients and controls had no effect. It was concluded that NZB treatment determines an accumulation of CD4+pSTAT1+, CD8+pSTAT1+, CD4+T-bet+, CD8+T-bet+ and CD4+STAT3+ T cells in peripheral blood that may account for the exacerbation of the disease observed in some patients after the discontinuation of the drug.

scholarly journals Quantitative analysis of CD4+CD25+FoxP3+ regulatory T-cells in canine atopic dermatitis in Korea

2020 ◽  
Vol 65 (No. 6) ◽  
pp. 250-257
Author(s):  
DJ Lee ◽  
TH Chung ◽  
C Park
Keyword(s):  
T Cells ◽  
Atopic Dermatitis ◽  
Regulatory T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Canine Atopic Dermatitis ◽  
Healthy Dogs ◽  
The Difference ◽  
Circulating T Cells

Recently, it was suggested that CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> Tregs (Regulatory T-cells) exist in canine skin, although their numbers were not significantly different between healthy and atopic dogs. In this study, we investigated whether Treg frequencies correlate with the clinical features of canine atopic dermatitis (cAD). The goal of this study was to compare and analyse the numbers of the circulating Tregs in atopic and healthy dogs. In the peripheral blood mononuclear cells (PBMC) of healthy dogs, Tregs defined as CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> Tregs in the peripheral blood ranged from 0.3% to 1.5%. By contrast, in atopic dogs, the same population ranged from 0.7% to 8.8%. The percentage of CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> Tregs in gated CD4<sup>+</sup> T-cells was significantly higher in the peripheral blood of dogs with atopic dermatitis (n = 9) than in the healthy controls (n = 8). The difference in the Treg levels (CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup>) (P = 0.012) between the atopic and the healthy groups was statistically significant. The circulating T-cells (phenotype CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> and CD4<sup>+</sup>FoxP3<sup>+</sup>) were increased significantly in the atopic dogs. The proportion of CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> Tregs of the atopic dogs decreased with advancing age. These findings suggest that changes in the Tregs may mediate the pathogenesis of CAD.

scholarly journals Precision engineering of an anti-HLA-A2 chimeric antigen receptor in regulatory T cells for transplant immune tolerance

2021 ◽  
Author(s):  
Yannick D. Muller ◽  
Leonardo M.R. Ferreira ◽  
Emilie Ronin ◽  
Patrick Ho ◽  
Vinh Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Chimeric Antigen Receptor ◽  
Mononuclear Cells ◽  
Antigen Receptor ◽  
Single Chain ◽  
Transplant Tolerance ◽  
Peripheral Blood Mononuclear

Infusion of regulatory T cells (Tregs) engineered with a chimeric antigen receptor (CAR) targeting donor-derived human leukocyte antigen (HLA) is a promising strategy to promote transplant tolerance. Here, we describe an anti-HLA-A2 CAR (A2-CAR) generated by grafting the complementarity-determining regions (CDRs) of a human monoclonal anti-HLA-A2 antibody into the framework regions of the Herceptin 4D5 single-chain variable fragment and fusing it with a CD28-zeta signaling domain. The CDR-grafted A2-CAR maintained the specificity of the original antibody. We then generated HLA-A2 mono-specific human CAR Tregs either by deleting the endogenous T-cell receptor (TCR) via CRISPR/Cas9 and introducing the A2-CAR using lentiviral transduction or by directly integrating the CAR construct into the TCR alpha constant locus using homology-directed repair. These A2-CAR+TCRdeficient human Tregs maintained both Treg phenotype and function in vitro. Moreover, they selectively accumulated in HLA-A2-expressing islets transplanted from either HLA-A2 transgenic mice or deceased human donors. A2-CAR+TCRdeficient Tregs did not impair the function of these HLA-A2+ islets, whereas similarly engineered A2-CAR+TCRdeficientCD4+ conventional T cells rejected the islets in less than 2 weeks. A2-CAR+TCRdeficient Tregs delayed graft-versus-host disease only in the presence of HLA-A2, expressed either by co-transferred peripheral blood mononuclear cells or by the recipient mice. Altogether, we demonstrate that genome-engineered mono-antigen-specific A2-CAR Tregs localize to HLA-A2-expressing grafts and exhibit antigen-dependent in vivo suppression, independent of TCR expression. These approaches may be applied towards developing precision Treg cell therapies for transplant tolerance.

scholarly journals Induction of CD4+CD25+ Regulatory T Cells from In Vitro Grown Human Mononuclear Cells by Sparteine Sulfate and Harpagoside

Biology ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 211 ◽  
Author(s):  
Nour Z. Atwany ◽  
Seyedeh-Khadijeh Hashemi ◽  
Manju Nidagodu Jayakumar ◽  
Mitzi Nagarkatti ◽  
Prakash Nagarkatti ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Mononuclear Cells ◽  
Cultured Cells ◽  
Inflammatory Responses ◽  
Human Peripheral Blood ◽  
Stimulation Index ◽  
Tgf Beta ◽  
Peripheral Blood Mononuclear

Regulatory T cells (Tregs) are key players in the regulation of inflammatory responses. In this study, two natural molecules, namely, sparteine sulfate (SS) and harpagoside (Harp), were investigated for their ability to induce Tregs in human peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from healthy volunteers and grown in the presence or absence of ConA, with TGF-beta, SS or Harp. Expression of the mRNA of FoxP3, TGF-beta, IL-10 and GAPDH was assessed via q-PCR. The expression of Treg markers including CD4, CD25, CD127 and FoxP3 was measured via flow cytometry. The secretion of IL-10 and TGF-beta by cultured cells was assessed by ELISA. Furthermore, the suppressive role of SS and Harp on PBMCs in vitro was tested via allogeneic mixed lymphocyte reaction (MLR). Data obtained show that both compounds increased the expression of FoxP3, TGF-beta and IL-10 mRNA in resting PBMCs but to a lesser extent in activated cells. Moreover, they significantly increased the percent of CD4+CD25+FoxP3+CD127− Tregs in activated and naïve PBMCs. Functionally, both compounds caused a significant reduction in the stimulation index in allogeneic MLR. Together, our data demonstrate for the first time that SS and Harp can induce human Tregs in vitro and therefore have great potential as anti-inflammatory agents.

No significant effect of orally administered chemokine receptor 1 antagonist on intercellular adhesion molecule-3 expression in relapsing—remitting multiple sclerosis patients

2010 ◽  
Vol 16 (3) ◽  
pp. 366-369 ◽  
Author(s):  
R. Reuβ ◽  
V. Schreiber ◽  
A. Klein ◽  
C. Infante-Duarte ◽  
M. Filippi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Peripheral Blood Mononuclear Cells ◽  
Chemokine Receptor ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Intercellular Adhesion ◽  
Peripheral Blood Mononuclear ◽  
Relapsing Remitting ◽  
Blood Mononuclear Cells ◽  
Relapsing Remitting Multiple Sclerosis

We investigated the expression of intercellular adhesion molecules ICAM-1 and ICAM-3 on peripheral blood mononuclear cells in a subgroup of 34 patients with relapsing-remitting multiple sclerosis who were treated orally with the chemokine receptor 1 antagonist BX 471 in a 16-week, randomised, double-blind, placebo-controlled phase II study. ICAM-1 and ICAM-3 expression was measured by flow cytometry at different time points during and after therapy and compared using multivariate analysis of variance and non-parametric Mann Whitney test. ICAM-3 expression on CD14 + peripheral blood mononuclear cells was increased in the verum group under therapy, but did not differ significantly between the verum and placebo groups. Most likely, this trend represents a small epiphenomenon only mediated by receptor cross-talk and feedback mechanisms.

scholarly journals Adiponectin/AdipoR1 Axis Promotes IL-10 Release by Human Regulatory T Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Patricia Ramos-Ramírez ◽  
Carina Malmhäll ◽  
Omar Tliba ◽  
Madeleine Rådinger ◽  
Apostolos Bossios
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Regulatory T Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Foxp3 Expression ◽  
P38 Map Kinase ◽  
Adiponectin Receptor ◽  
Peripheral Blood Mononuclear ◽  
Cytokine Milieu

BackgroundAdiponectin is an important immunomodulatory mediator in inflammatory conditions. While we previously showed that adiponectin receptor 1 (AdipoR1) is expressed in murine regulatory T cells (Tregs), its expression in human Tregs remain unknown. Here, we examined the expression of AdipoR1 in human Tregs and whether its ligand, globular adiponectin (gAd) affects the Treg ability to secrete IL-10 and the role of Type 2 (T2) inflammation in such process.MethodsHuman Tregs from peripheral blood were analyzed by flow cytometry for AdipoR1, Helios and IL-10 expression. CD4+ T cells enriched from peripheral blood mononuclear cells (PBMCs) were cultured in the presence or the absence of gAd or the chemical adiponectin receptor agonist, AdipoRon, or in a T2 cytokine milieu. Flow cytometry was then used to assess intracellular IL-10, IL-10 secreting cells, FOXP3 and Helios expression, and phosphorylated p38 MAP kinase (MAPK). IL-10 levels in CD4+ T cell supernatants were quantified by ELISA.ResultsWe found that a subset of human Tregs expressed AdipoR1. Importantly, more Helios- cells expressed AdipoR1 than Helios+ cells. Likewise, there was a higher frequency of IL-10+ cells within Helios- AdipoR1+ Tregs compared to Helios+ AdipoR1+ Tregs. In contrast, the IL-10 mean fluorescence intensity (MFI) was higher in Helios+ AdipoR1+ Tregs compared to Helios-AdipoR1+ Tregs. When human CD4+ T cells were treated with gAd or AdipoRon, a significant increase in IL-10 secretion, FOXP3 expression, and p38 MAPK phosphorylation was observed in Helios- AdipoR1+ Tregs. Interestingly, gAd under T2 cytokine milieu significantly increased the intracellular levels of IL-10, mainly in Helios+ AdipoR1+ Tregs, and IL-10 levels in supernatants of CD4+ T cells.ConclusionsCollectively, our findings suggest that adiponectin/AdipoR1 axis promotes IL-10 release by Tregs, mainly in Helios- Tregs, and the effect was amplified by T2 inflammation in Helios+ Tregs.

High levels of thyroid hormone impair regulatory T cells function via reduced PD-1 expression

2021 ◽  
Author(s):  
Yi Zhong ◽  
Ting-Ting Lu ◽  
Xiao-Mei Liu ◽  
Bing-Li Liu ◽  
Yun Hu ◽  
...  
Keyword(s):  
T Cells ◽  
Thyroid Hormone ◽  
Regulatory T Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear

Abstract Context Regulatory T cells (Tregs) dysfunction plays an important role in the development and progression of Graves’ disease (GD). Programmed cell death 1 (PD-1) prompts FoxP3 in Tregs expression and enhances the suppressive activity of Tregs. Whether abnormal expression of PD-1 contributes to the breakdown of Tregs and the role of thyroid hormone in the PD-1 expression of Tregs in GD remain substantially undefined. Objective To evaluate the role of PD-1 in Tregs function and triiodothyronine (T3) in PD-1 expression in patients with GD and mice treated with T3. Methods We recruited 30 patients with GD and 30 healthy donors. PD-1 expression in Tregs and Tregs function were determined. To evaluate the effects of thyroid hormone on PD-1 expression in Tregs, we used T3 for the treatment of human peripheral blood mononuclear cells (PBMCs). We then treated mice with T3 to confirm the effect of thyroid hormone on PD-1 expression in Tregs and Tregs function in vivo. Results PD-1 expression in Tregs and the suppressive function of Tregs significantly decreased in patients with GD. T3 reduced PD-1 expression in human Tregs in a concentration- and time-dependent manner in vitro. High levels of circulating T3 reduced PD-1 expression in Tregs, impaired Tregs function, and disrupted T-helper cell (Th1 and Th2) balance in mice treated with T3. Conclusions Tregs dysfunction in GD patients might be due to down-regulation of PD-1 expression in Tregs induced by high levels of serum T3.

scholarly journals Peripheral blood mononuclear cells and regulatory T cells in acute viral hepatitis.

Gut ◽  
1985 ◽  
Vol 26 (7) ◽  
pp. 739-744 ◽  
Author(s):  
V Barnaba ◽  
E Tamburrini ◽  
V Laghi ◽  
R Cauda ◽  
M Levrero ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Viral Hepatitis ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Acute Viral Hepatitis ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells
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