scholarly journals Deficient CD4+ CD25+ FOXP3+ T regulatory cells in acquired aplastic anemia

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1603-1606 ◽  
Author(s):  
Elena E. Solomou ◽  
Katayoun Rezvani ◽  
Stephan Mielke ◽  
Daniela Malide ◽  
Keyvan Keyvanfar ◽  
...  
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
T Regulatory Cells ◽  
T Cell Development ◽  
Foxp3 Expression ◽  
Mrna Levels ◽  
Regulatory Cells ◽  
Protein Levels ◽  
Almost All ◽  
And Function

Abstract Regulatory T cells are believed to control the development and progression of autoimmunity by suppressing autoreactive T cells. Decreased numbers of CD4+CD25+ FOXP3+ T cells (Tregs) are associated with impaired immune homeostasis and development of autoimmune diseases. The transcription factors FOXP3 and NFAT1 have key roles in regulatory T-cell development and function. We show that Tregs are decreased at presentation in almost all patients with aplastic anemia; FOXP3 protein and mRNA levels also are significantly lower in patients with aplastic anemia and NFAT1 protein levels are decreased or absent. Transfection of FOXP3-deficient CD4+CD25+ T cells from patients with a plasmid encoding wild-type NFAT1 resulted in increased FOXP3 expression in these cells. By NFAT1 knockdown in CD4+CD25+ T cells, FOXP3 expression was decreased when NFAT1 expression was decreased. Our findings indicate that decreased NFAT1 could explain low FOXP3 expression and diminished Treg frequency in aplastic anemia. Treg defects are now implicated in autoimmune marrow failure.

FOXP3-Positive Regulatory T-Cells in Acquired Aplastic Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2248-2248 ◽  
Author(s):  
Elena E. Solomou ◽  
Katayoun Rezvani ◽  
Stephan Mielke ◽  
Daniela Malide ◽  
Valeria Visconte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Aplastic Anemia ◽  
Immunosuppressive Treatment ◽  
Foxp3 Expression ◽  
Mrna Levels ◽  
Healthy Controls ◽  
Protein Levels ◽  
Immune Mediated

Abstract CD4+CD25+ regulatory T cells (Treg) have been hypothesized to control the development and progression of autoimmunity by suppressing autoreactive T cells. Treg are characterized by constitutive expression of membrane CD25 and intracellular expression of the transcription factor forkhead box (FOX) P3. FOXP3 and NF-AT1 have key roles in regulatory T-cell development and function: induction of FOXP3 in naïve T cells by gene transfer results in gain of a regulatory phenotype, and NF-AT1 modulates transcription of FOXP3. Treg display their suppressive properties on CD4+ CD25- T cells when activated via the T cell receptor or Toll-like receptor-2 (TLR2). Decreased numbers of FOXP3-positive regulatory Tregs have been associated with impaired immune homeostasis. Treg numbers are deficient in patients with active systemic lupus erythematosus, GVHD, and autoimmune hepatitis; in multiple sclerosis, decreased FOXP3 impairs Treg function. Acquired aplastic anemia (AA), the paradigm of immune mediated bone marrow failure syndromes, is characterized by immune-mediated destruction of hematopoietic stem cells. To examine expression of CD4+CD25+ T-cells in this disease, peripheral blood mononuclear cells from AA patients, sampled at diagnosis and prior to immunosuppressive therapy (n=18), were examined by flow cytometry: CD4+CD25hi+ T-cells were markedly reduced or absent in patients compared to healthy controls (n = 12, 0.08± 0.01 vs 0.4± 0.1%, p=0.001). CD4+CD25hi+FOXP3+ T-cells were also significantly lower in patients (0.05± 0.01 vs 0.32± 0.1, p=0.001). By immunoblot, we observed significantly decreased and often undetectable FOXP3 protein levels in CD4+CD25+ T cells from patients (n=8) compared to controls (n=6). Low FOXP3 protein levels correlated with decreased FOXP3 mRNA levels, as measured by RT-PCR and quantitative real-time PCR experiments (n=5, p=0.03). There were no differences in TLR2 in immunoblots between patients and healthy controls despite differences in FOXP3 expression. Patients (n=8) with low FOXP3 levels also showed decreased or absent NF-AT1 protein levels. These data collectively implicate a transcriptional mechanism for FOXP3 down-regulation. In confocal microscopy, purified CD4+CD25+ T cells from patients (n=5) showed undetectable NF-AT1 and FOXP3 levels as compared to controls (n=3). Four patients studied 3–6 months after first sampling and post-immunosuppressive treatment showed increased Tregs and FOXP3 expression; four further patients in complete remission after immunosuppressive treatment had increased CD4+CD25hi+ T-cells as compared to treatment-naïve patients. CD4+CD25+FOXP3+ regulatory T-cells are decreased in most patients with AA, probably through transcriptional regulation; decreased NFAT1 could explain low FOXP3 expression and Treg frequency. Treg employed as cellular therapy in a murine model of immune-mediated AA can prevent T cell-mediated marrow destruction (Chen J and Young NS, unpublished data). Treg defects are now implicated in autoimmune marrow failure in aplastic anemia.

scholarly journals Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease

2011 ◽  
Vol 208 (10) ◽  
pp. 2069-2081 ◽  
Author(s):  
Jeffrey VanValkenburgh ◽  
Diana I. Albu ◽  
Chandra Bapanpally ◽  
Sarah Casanova ◽  
Danielle Califano ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cd4 T Cells ◽  
T Regulatory Cells ◽  
Critical Role ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Regulatory Cells ◽  
Genes Encoding ◽  
Inflammatory Bowel

Dysregulated CD4+ T cell responses and alterations in T regulatory cells (Treg cells) play a critical role in autoimmune diseases, including inflammatory bowel disease (IBD). The current study demonstrates that removal of Bcl11b at the double-positive stage of T cell development or only in Treg cells causes IBD because of proinflammatory cytokine-producing CD4+ T cells infiltrating the colon. Provision of WT Treg cells prevented IBD, demonstrating that alterations in Treg cells are responsible for the disease. Furthermore, Bcl11b-deficient Treg cells had reduced suppressor activity with altered gene expression profiles, including reduced expression of the genes encoding Foxp3 and IL-10, and up-regulation of genes encoding proinflammatory cytokines. Additionally, the absence of Bcl11b altered the induction of Foxp3 expression and reduced the generation of induced Treg cells (iTreg cells) after Tgf-β treatment of conventional CD4+ T cells. Bcl11b bound to Foxp3 and IL-10 promoters, as well as to critical conserved noncoding sequences within the Foxp3 and IL-10 loci, and mutating the Bcl11b binding site in the Foxp3 promoter reduced expression of a luciferase reporter gene. These experiments demonstrate that Bcl11b is indispensable for Treg suppressor function and for maintenance of optimal Foxp3 and IL-10 gene expression, as well as for the induction of Foxp3 expression in conventional CD4+ T cells in response to Tgf-β and generation of iTreg cells.

ATG-induced expression of FOXP3 in human CD4+ T cells in vitro is associated with T-cell activation and not the induction of FOXP3+ T regulatory cells

Blood ◽  
2009 ◽  
Vol 114 (24) ◽  
pp. 5003-5006 ◽  
Author(s):  
Raewyn Broady ◽  
Jie Yu ◽  
Megan K. Levings
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
Cellular Therapy ◽  
Foxp3 Expression ◽  
Regulatory Cells ◽  
T Effector Cells

Abstract Several recent reports have suggested that in vitro exposure of CD4+ T cells to rabbit antithymocyte globulin (rATG), which is commonly used to prevent and treat graft-versus-host disease and allograft rejection, is an effective method to induce CD4+CD25+FOXP3+ T regulatory cells (Tregs). We and others, however, have shown that FOXP3 is also expressed in activated T cells. We therefore investigated whether the induction of FOXP3 expression by rATG resulted in a stable population of suppressive Tregs. We found that exposure of peripheral blood mononuclear cells (PBMCs) or conventional T cells to rATG resulted in induction of transient rather than stable expression of CD25 and FOXP3. Furthermore, rATG-treated T effector cells acquired neither an immunosuppressive profile of cytokine production nor suppressive capacity, even at the time of maximal FOXP3 expression. These findings indicate that the notion that rATG can be used to induce Tregs in vitro for cellular therapy in vivo should be re-evaluated.

Chronic Lymphocytic Leukaemia Drives the Production of T Regulatory Cells From the CD4+ CD25- Compartment with a CD27high/CD127 Low Phenotype.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2330-2330
Author(s):  
Karen Piper ◽  
Mamtha Karanth ◽  
Andrew McLarnon ◽  
Emma Kalk ◽  
Naeem Khan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
T Regulatory Cells ◽  
Lymphocytic Leukaemia ◽  
Conflicts Of Interest ◽  
Fold Increase ◽  
Foxp3 Expression ◽  
Regulatory Cells ◽  
Pre Treatment ◽  
Cellular And Humoral Immunity ◽  
And Function

Abstract Abstract 2330 Poster Board II-307 Patients with chronic lymphocytic leukaemia (CLL) have defects in both cellular and humoral immunity including changes in the numbers and function of T regulatory cells (Tregs). The identification of Tregs is an ever-evolving field and in this study we readdressed the phenotype using the markers CD25, FoxP3 and CD127-/lo and confirmed function by classical suppressor assays in CLL patients on and off treatment. Using the combination CD4 and FoxP3 we observed increased Treg frequencies in CLL patients, in particular with advanced disease, supporting previous studies showing an increase in Tregs in CLL. However in contrast to previous studies, there was no increase in the CD25+ FoxP3+ population in CLL patients rather the increase in FoxP3 expression occurred in the CD25- compartment of CLL patients. Interestingly CLL induced a 7-fold increase in the expression of FoxP3 in CD4+CD25- T cells following short-term co-culture. The T regulatory cells in CLL patients had a significantly higher expression of CD27 compared to healthy controls and although CD127 expression was low in both healthy and CLL patients it was significantly lower in CLL patients. Fludarabine treatment initially induced increased expression of FoxP3 in the CD4+ T cell compartment but this declined gradually to reach levels below that pre-treatment. Here we propose that CLL drives the production of Tregs from the CD4+CD25- compartment as has been shown recently in Non-Hodgkins Lymphoma (NHL) and the mechanism of induction could provide alternative avenues for treatment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Dysfunctional T regulatory cells in multiple myeloma

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 301-304 ◽  
Author(s):  
Rao H. Prabhala ◽  
Paola Neri ◽  
Jooeun E. Bae ◽  
Pierfrancesco Tassone ◽  
Masood A. Shammas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
T Regulatory Cells ◽  
T Cell Responses ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Cell Responses ◽  
Healthy Donors ◽  
And Function

Abstract Multiple myeloma (MM) is characterized by the production of monoclonal immunoglobulin and is associated with suppressed uninvolved immunoglobulins and dysfunctional T-cell responses. The biologic basis of this dysfunction remains ill defined. Because T regulatory (Treg) cells play an important role in suppressing normal immune responses, we evaluated the potential role of Treg cells in immune dysfunction in MM. We observed a significant increase in CD4+CD25+ T cells in patients with monoclonal gammopathy of undetermined significance (MGUS) and in patients with MM compared with healthy donors (25% and 26%, respectively, vs 14%); however, Treg cells as measured by FOXP3 expression are significantly decreased in patients with MGUS and MM compared with healthy donors. Moreover, even when they are added in higher proportions, Treg cells in patients with MM and MGUS are unable to suppress anti-CD3–mediated T-cell proliferation. This decreased number and function of Treg cells in MGUS and in MM may account, at least in part, for the nonspecific increase in CD4+CD25+ T cells, thereby contributing to dysfunctional T-cell responses.

scholarly journals Multiple sclerosis patients have reduced resting and increased activated CD4+CD25+FOXP3+T regulatory cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nirupama D. Verma ◽  
Andrew D. Lam ◽  
Christopher Chiu ◽  
Giang T. Tran ◽  
Bruce M. Hall ◽  
...  
Keyword(s):  
T Cells ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
Effector Memory ◽  
Regulatory Cells ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Treg Population ◽  
Multiple Sclerosis Patients ◽  
Population Iii

AbstractResting and activated subpopulations of CD4+CD25+CD127loT regulatory cells (Treg) and CD4+CD25+CD127+ effector T cells in MS patients and in healthy individuals were compared. Peripheral blood mononuclear cells isolated using Ficoll Hypaque were stained with monoclonal antibodies and analysed by flow cytometer. CD45RA and Foxp3 expression within CD4+ cells and in CD4+CD25+CD127loT cells identified Population I; CD45RA+Foxp3+, Population II; CD45RA−Foxp3hi and Population III; CD45RA−Foxp3+ cells. Effector CD4+CD127+ T cells were subdivided into Population IV; memory /effector CD45RA− CD25−Foxp3− and Population V; effector naïve CD45RA+CD25−Foxp3−CCR7+ and terminally differentiated RA+ (TEMRA) effector memory cells. Chemokine receptor staining identified CXCR3+Th1-like Treg, CCR6+Th17-like Treg and CCR7+ resting Treg. Resting Treg (Population I) were reduced in MS patients, both in untreated and treated MS compared to healthy donors. Activated/memory Treg (Population II) were significantly increased in MS patients compared to healthy donors. Activated effector CD4+ (Population IV) were increased and the naïve/ TEMRA CD4+ (Population V) were decreased in MS compared to HD. Expression of CCR7 was mainly in Population I, whereas expression of CCR6 and CXCR3 was greatest in Populations II and intermediate in Population III. In MS, CCR6+Treg were lower in Population III. This study found MS is associated with significant shifts in CD4+T cells subpopulations. MS patients had lower resting CD4+CD25+CD45RA+CCR7+ Treg than healthy donors while activated CD4+CD25hiCD45RA−Foxp3hiTreg were increased in MS patients even before treatment. Some MS patients had reduced CCR6+Th17-like Treg, which may contribute to the activity of MS.

scholarly journals Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110097
Author(s):  
Kui Cui ◽  
Fan Yang ◽  
Turan Tufan ◽  
Muhammad U. Raza ◽  
Yanqiang Zhan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcription Factors ◽  
Disease Model ◽  
Neuronal Loss ◽  
Mrna Levels ◽  
Gene Therapies ◽  
Protein Levels ◽  
Dopaminergic Systems ◽  
And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

scholarly journals DBC1 (Deleted in Breast Cancer 1) modulates the stability and function of the nuclear receptor Rev-erbα

2013 ◽  
Vol 451 (3) ◽  
pp. 453-461 ◽  
Author(s):  
Claudia C. S. Chini ◽  
Carlos Escande ◽  
Veronica Nin ◽  
Eduardo N. Chini
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptor ◽  
Clock Genes ◽  
Mrna Levels ◽  
Protein Levels ◽  
The Stability ◽  
And Function ◽  
Interfering Rna ◽  
In Cells

The nuclear receptor Rev-erbα has been implicated as a major regulator of the circadian clock and integrates circadian rhythm and metabolism. Rev-erbα controls circadian oscillations of several clock genes and Rev-erbα protein degradation is important for maintenance of the circadian oscillations and also for adipocyte differentiation. Elucidating the mechanisms that regulate Rev-erbα stability is essential for our understanding of these processes. In the present paper, we report that the protein DBC1 (Deleted in Breast Cancer 1) is a novel regulator of Rev-erbα. Rev-erbα and DBC1 interact in cells and in vivo, and DBC1 modulates the Rev-erbα repressor function. Depletion of DBC1 by siRNA (small interfering RNA) in cells or in DBC1-KO (knockout) mice produced a marked decrease in Rev-erbα protein levels, but not in mRNA levels. In contrast, DBC1 overexpression significantly enhanced Rev-erbα protein stability by preventing its ubiquitination and degradation. The regulation of Rev-erbα protein levels and function by DBC1 depends on both the N-terminal and C-terminal domains of DBC1. More importantly, in cells depleted of DBC1, there was a dramatic decrease in circadian oscillations of both Rev-erbα and BMAL1. In summary, our data identify DBC1 as an important regulator of the circadian receptor Rev-erbα and proposes that Rev-erbα could be involved in mediating some of the physiological effects of DBC1.

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