scholarly journals Low-dose decitabine modulates T cell homeostasis and restores immune tolerance in immune thrombocytopenia

Blood ◽  
2021 ◽  
Author(s):  
Panpan Han ◽  
Yu Hou ◽  
Yajing Zhao ◽  
Yang Liu ◽  
Yunqi Sun ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Tolerance ◽  
Immune Thrombocytopenia ◽  
Low Dose ◽  
Treg Cells ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Cytokine Analysis ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Our previous clinical study demonstrated that low-dose decitabine showed sustained responses in nearly half of refractory immune thrombocytopenia (ITP) patients. The long-term efficacy of decitabine in ITP is not likely due to its simple role in increasing platelet production. Whether decitabine has the potential to restore immune tolerance in ITP is unknown. In this study, we analyzed the effect of decitabine on T cell subpopulations in ITP in vitro and in vivo. We found that low-dose decitabine promoted the generation and differentiation of regulatory T (Treg) cells, and augmented their immunosuppressive function. Splenocytes from CD61 knockout mice immunized with CD61+ platelets were transferred into severe combined immunodeficient (SCID) mouse recipients to induce a murine model of ITP. Low-dose decitabine alleviated thrombocytopenia and restored the balance between Treg and helper T (Th) cells in active ITP mice. Treg deletion and depletion offset the effect of decitabine in restoring CD4+ T cell subpopulations in ITP mice. For patients who received low-dose decitabine, the quantity and function of Treg cells were substantially improved, whereas Th1 and Th17 cells were suppressed compared with the pretreatment levels. Next-generation RNA sequencing and cytokine analysis showed that low-dose decitabine rebalanced T cell homeostasis, decreased proinflammatory cytokines, and down-regulated phosphorylated STAT3 in ITP patients. STAT3 inhibition analysis suggested that low-dose decitabine might restore Treg cells by inhibiting STAT3 activation. In conclusion, our data indicated that the immunomodulatory effect of decitabine provided one possible mechanistic explanation for the sustained response achieved by low-dose decitabine in ITP.

scholarly journals Differential Levels of Regulatory T Cells and T-Helper-17 Cells in Women With Early and Advanced Endometriosis

2019 ◽  
Vol 104 (10) ◽  
pp. 4715-4729 ◽  
Author(s):  
Khaleque N Khan ◽  
Kazuo Yamamoto ◽  
Akira Fujishita ◽  
Hideki Muto ◽  
Akemi Koshiba ◽  
...  
Keyword(s):  
T Cell ◽  
Th17 Cells ◽  
Treg Cells ◽  
Lower Percentage ◽  
T Helper ◽  
T Helper 17 ◽  
Control Subjects ◽  
Cell Subpopulations ◽  
American Society ◽  
T Cell Subpopulations

Abstract Context Regulatory T (Treg) cells and T-helper-17 (Th17) cells may be involved in endometriosis. Information on the pattern of change in the percentages of Treg and Th17 cells in the peripheral blood (PB) and peritoneal fluid (PF) of women with early and advanced endometriosis is unclear. Objective To investigate the pattern of change in the percentages of Treg and Th17 cells in the PB and PF of women with early and advanced endometriosis. Methods We recruited 31 women with laparoscopically and histologically confirmed, revised American Society of Reproductive Medicine stage I-II endometriosis, 39 women with stage III-IV endometriosis, and 36 control subjects without visible endometriosis. PB and PF samples were collected and T-cell subpopulations analyzed by flow cytometry using specific monoclonal antibodies recognizing CD4+, CD25+, FOXP3+, and IL-17A+ markers. PF concentrations of TGF-β and IL-17 were measured by ELISA. Results The percentages of CD25+FOXP3+ Treg cells within the CD4+ T-cell population were significantly higher in the PF of women with advanced endometriosis than in either early endometriosis or in control subjects (P < 0.05 for both). A persistently lower percentage of CD4+IL-17A+ Th17 cells was found in both PB and PF of women with early and advanced endometriosis. Compared with IL-17 levels, PF levels of TGF-β were significantly higher in women with endometriosis (P = 0.01). Conclusion Our findings reconfirmed the current speculation that endometriosis is related to alteration of Treg and Th17 cells in the pelvis causing survival and implantation of ectopic endometrial lesions.

scholarly journals The Interaction of Sodium and Zinc in the Priming of T Cell Subpopulations Regarding Th17 and Treg Cells

2020 ◽  
Vol 64 (2) ◽  
pp. 1900245 ◽  
Author(s):  
Sophie Dünkelberg ◽  
Martina Maywald ◽  
Anne Kristina Schmitt ◽  
Tanja Schwerdtle ◽  
Sören Meyer ◽  
...  
Keyword(s):  
T Cell ◽  
Treg Cells ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

scholarly journals Indirubin modulates CD4+T-cell homeostasis via PD1/PTEN/AKT signalling pathway in immune thrombocytopenia

2019 ◽  
Vol 23 (3) ◽  
pp. 1885-1898 ◽  
Author(s):  
Yajing Zhao ◽  
Panpan Han ◽  
Lei Liu ◽  
Xiaojie Wang ◽  
Pengcheng Xu ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Thrombocytopenia ◽  
Signalling Pathway ◽  
Cd4 T Cell ◽  
T Cell Homeostasis ◽  
Cell Homeostasis

scholarly journals Low-Dose Interleukin-2 Therapy Restores Regulatory T Cell Homeostasis in Patients with Chronic Graft-Versus-Host Disease

2013 ◽  
Vol 5 (179) ◽  
pp. 179ra43-179ra43 ◽  
Author(s):  
K.-i. Matsuoka ◽  
J. Koreth ◽  
H. T. Kim ◽  
G. Bascug ◽  
S. McDonough ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Versus Host Disease ◽  
Regulatory T Cell ◽  
Low Dose ◽  
Interleukin 2 ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Host Disease ◽  
Graft Versus Host

scholarly journals PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy

Blood ◽  
2017 ◽  
Vol 129 (15) ◽  
pp. 2186-2197 ◽  
Author(s):  
Takeru Asano ◽  
Yusuke Meguri ◽  
Takanori Yoshioka ◽  
Yuriko Kishi ◽  
Miki Iwamoto ◽  
...  
Keyword(s):  
T Cell ◽  
Regulatory T Cell ◽  
Low Dose ◽  
Interleukin 2 ◽  
Murine Models ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Key Points ◽  
Treg Differentiation

Key Points IL-2 induces expression of PD-1 on Tregs, and PD-1 blockade promotes Treg differentiation and apoptosis. PD-1 regulates IL-2–induced Treg proliferation and prolongs Treg survival in murine models and in patients receiving low-dose IL-2 therapy.

scholarly journals Immunoregulatory therapy in anti-neutrophil cytoplasmic antibody-associated vasculitis: Low-dose Interleukin-2 therapy increases the reduced Treg cells

2021 ◽  
Author(s):  
Ruihe Wu ◽  
Yanfei Mu ◽  
Xiangcong Zhao ◽  
Jinfang Zhao ◽  
Tingting Ding ◽  
...  
Keyword(s):  
T Cell ◽  
Autoimmune Diseases ◽  
Disease Activity ◽  
Immune Tolerance ◽  
Low Dose ◽  
Interleukin 2 ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Clinical Indicators

Abstract Objective: The breakdown of immune tolerance caused by dysfunctional CD4+T cells is one of the key mechanisms to participate in the pathogenesis and progression of autoimmune diseases, especially the reduced regulatory T (Treg) cell is associated with the breakdown of immune tolerance. Low-dose Interleukin-2 (IL-2) therapy has been confirmed to be a potential therapy to treat autoimmune diseases by selectively expanding Treg cells to restore the immune tolerance. However, it is still unclear whether Treg cells play an important role in the progression of anti-neutrophil cytoplasmic antibody-(ANCA)-associated vasculitis (AAV), and whether low-dose IL-2 therapy contributes to restore the immune tolerance and promote the remission of disease in AAV. The aim of our study is to explore the role of Treg cells in the progression of AAV and evaluate the efficacy of low-dose IL-2 therapy on AAV. Methods: We collected the clinical data of 39 patients with AAV (including 12 who received subcutaneous low-dose IL-2 therapy combined with conventional therapies) and 65 healthy controls (HCs) to compare the differences of the absolute number of CD4 + T cell subsets, and then analyze the relationship between these cells and the clinical indicators of disease activity. In addition, we investigated the changes of CD4 + T cell subsets and clinical indicators before and after the treatment of low-dose IL-2 therapy. Results: Patients with AAV had reduced peripheral Treg cells than HCs (P<0.001), which were negatively correlated with the clinical indicators of disease activity and organ injury, and those patients with high disease activity exhibited lower level peripheral Treg cells(P=0.002). The low-dose IL-2 therapy significantly increased the reduced Treg cells in patients with AAV compared with the baseline values (P=0.001) to promote the remission of disease. Conclusion: The reduced peripheral blood Treg cells participated in the imbalance of immune in patients with AAV and were related to the progression of disease. Low-dose IL-2, as an immunoregulatory therapy, increases the reduced Treg cells to restore the immune tolerance and promote the remission of AAV.

scholarly journals Dysregulation of IL-15-mediated T-cell homeostasis in TGF-β dominant-negative receptor transgenic mice

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2789-2795 ◽  
Author(s):  
Philip J. Lucas ◽  
Seong-Jin Kim ◽  
Crystal L. Mackall ◽  
William G. Telford ◽  
Yu-Waye Chu ◽  
...  
Keyword(s):  
T Cell ◽  
Memory Cell ◽  
Surface Expression ◽  
Dominant Negative ◽  
Negative Regulator ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Memory T Cell ◽  
Positive Effects ◽  
T Cell Subpopulations

AbstractT-cell subpopulations, defined by their expression of CD4, CD8, naive, and memory cell-surface markers, occupy distinct homeostatic compartments that are regulated primarily by cytokines. CD8+ memory T cells, as defined by CD44hi surface expression, are dependent on IL-15 as a positive regulator of their homeostatic maintenance. Manipulation of IL-15 signaling through gene aberration, overexpression, or receptor alterations has been shown to dramatically affect T-cell homeostasis, with overexpression leading to fatal leukemia. Here we show that TGF-β is the critical negative regulator of murine CD8+ memory T-cell homeostasis with direct opposition to the positive effects of IL-15. This negative regulation is mediated, at least in part, by the ability of TGF-β to modulate expression of the β-chain of the IL-15 receptor, thus establishing a central axis between these 2 cytokines for homeostatic control of CD8+ memory T-cell populations. These data establish TGF-β as a critical and dominant tumor-suppressor pathway opposing IL-15-mediated CD8+ T-cell expansion and potential malignant transformation.

scholarly journals Decreased numbers and sex-based differences of circulating regulatory T cells in patients with seropositive undifferentiated arthritis

2021 ◽  
Vol 12 ◽  
pp. 204062232098672
Author(s):  
Hong-Qing Niu ◽  
Chenrui Yuan ◽  
Chenglan Yan ◽  
Na Li ◽  
Yuan-Sheng Lei ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Flow Cytometric Analysis ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Joint Disease ◽  
Healthy Controls ◽  
Undifferentiated Arthritis ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Aims: CD4+ T cells play crucial roles as both mediators and regulators of the pathogenesis of rheumatoid arthritis (RA). However, the characteristics of CD4+ T cell subpopulations in the earliest stage of RA development remain unclear. Hence, we determined the proportions and absolute counts of circulating CD4+ T cell subsets in patients with seropositive undifferentiated arthritis (SUA), the early and preclinical stage of RA. Methods: Peripheral blood samples and clinical information were collected from 177 patients with SUA, 104 patients with RA, and 120 healthy controls. All patients were newly diagnosed and untreated. Proportions and absolute counts of CD4+ T cell subpopulations were determined by flow cytometric analysis. Results: In patients with SUA, percentages and absolute counts of circulating regulatory T (Treg) cells were decreased significantly and Th17/Treg cell ratios were abnormally increased, whereas Th17 cell numbers were similar to those in healthy controls. In addition, sex-based differences in circulating Treg cells were observed, with female SUA patients having lower proportions and absolute counts of Treg cells than those in males. Moreover, female patients with SUA had higher erythrocyte sedimentation rates and 28-joint Disease Activity Scores than those in males. Conclusion: Immune tolerance deficiency resulting from an abnormal reduction in circulating Treg cells might be the most crucial immunological event in the earliest stage of RA. The sex-specific disparity in Treg cells should also be considered for immunoregulatory and preventive strategies targeting early RA.

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