scholarly journals Compromised Function of Regulatory T Cells in Rheumatoid Arthritis and Reversal by Anti-TNFα Therapy

2004 ◽  
Vol 200 (3) ◽  
pp. 277-285 ◽  
Author(s):  
Michael R. Ehrenstein ◽  
Jamie G. Evans ◽  
Animesh Singh ◽  
Samantha Moore ◽  
Gary Warnes ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Significant Rise ◽  
Activated T Cells ◽  
Reactive Protein ◽  
Suppressive Phenotype ◽  
Factor Α

Regulatory T cells have been clearly implicated in the control of disease in murine models of autoimmunity. The paucity of data regarding the role of these lymphocytes in human autoimmune disease has prompted us to examine their function in patients with rheumatoid arthritis (RA). Regulatory (CD4+CD25+) T cells isolated from patients with active RA displayed an anergic phenotype upon stimulation with anti-CD3 and anti-CD28 antibodies, and suppressed the proliferation of effector T cells in vitro. However, they were unable to suppress proinflammatory cytokine secretion from activated T cells and monocytes, or to convey a suppressive phenotype to effector CD4+CD25− T cells. Treatment with antitumor necrosis factor α (TNFα; Infliximab) restored the capacity of regulatory T cells to inhibit cytokine production and to convey a suppressive phenotype to “conventional” T cells. Furthermore, anti-TNFα treatment led to a significant rise in the number of peripheral blood regulatory T cells in RA patients responding to this treatment, which correlated with a reduction in C reactive protein. These data are the first to demonstrate that regulatory T cells are functionally compromised in RA, and indicate that modulation of regulatory T cells by anti-TNFα therapy may be a further mechanism by which this disease is ameliorated.

A new approach to the role of IL-7 and TGF-ß in the in vitro generation of thymus-derived CD4+CD25+Foxp3+ regulatory T cells

Cytokine ◽  
2018 ◽  
Vol 102 ◽  
pp. 107-116 ◽  
Author(s):  
Anna Bieńkowska ◽  
Ewelina Kiernozek ◽  
Ewa Kozlowska ◽  
Łukasz Bugajski ◽  
Nadzieja Drela
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
New Approach

scholarly journals Growth Arrest-Specific 6 Enhances the Suppressive Function of CD4+CD25+Regulatory T Cells Mainly through Axl Receptor

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Guang-ju Zhao ◽  
Jia-yi Zheng ◽  
Jia-lan Bian ◽  
Long-wang Chen ◽  
Ning Dong ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Regulatory T Cells ◽  
Growth Arrest ◽  
Mrna Levels ◽  
Suppressive Function ◽  
Naturally Occurring ◽  
Tam Receptors

Background.Growth arrest-specific (Gas) 6 is one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), and its role as an immune modulator has been recently emphasized. Naturally occurring CD4+CD25+regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study was designed to investigate whether Tregs express TAM receptors and the potential role of Gas6-TAM signal in regulating the suppressive function of Tregs.Methods.The protein and mRNA levels of TAM receptors were determined by using Western blot, immunofluorescence, flow cytometry, and RT-PCR. Then, TAM receptors were silenced using targeted siRNA or blocked with specific antibody. The suppressive function of Tregs was assessed by using a CFSE-based T cell proliferation assay. Flow cytometry was used to determine the expression of Foxp3 and CTLA4 whereas cytokines secretion levels were measured by ELISA assay.Results.Tregs express both Axl and Mertk receptors. Gas6 increases the suppressive function of Tregs in vitro and in mice. Both Foxp3 and CTLA-4 expression on Tregs are enhanced after Gas6 stimulation. Gas6 enhances the suppressive activity of Tregs mainly through Axl receptor.Conclusion. Gas6 has a direct effect on the functions of CD4+CD25+Tregs mainly through its interaction with Axl receptor.

scholarly journals Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism

2019 ◽  
Vol 116 (39) ◽  
pp. 19600-19608 ◽  
Author(s):  
Sami B. Kanaan ◽  
Oyku Sensoy ◽  
Zhen Yan ◽  
Vijayakrishna K. Gadi ◽  
Michael L. Richardson ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Genetic Background ◽  
Mendelian Inheritance ◽  
Cross Reactivity ◽  
Genetic Contribution ◽  
Hla Dq ◽  
Microchimeric Cell

HLA class II genes provide the strongest genetic contribution to rheumatoid arthritis (RA). HLA-DRB1 alleles encoding the sequence DERAA are RA-protective. Paradoxically, RA risk is increased in women with DERAA+ children born prior to onset. We developed a sensitive qPCR assay specific for DERAA, and found 53% of DERAA−/− women with RA had microchimerism (Mc; pregnancy-derived allogeneic cells) carrying DERAA (DERAA-Mc) vs. 6% of healthy women. DERAA-Mc quantities correlated with an RA-risk genetic background including DERAA-binding HLA-DQ alleles, early RA onset, and aspects of RA severity. CD4+ T cells showed stronger response against DERAA+ vs. DERAA− allogeneic cell lines in vitro, in line with an immunogenic role of allogeneic DERAA. Results indicate a model where DERAA-Mc activates DERAA-directed T cells that are naturally present in DERAA−/− individuals and can have cross-reactivity against joint antigens. Moreover, we provide an explanation for the enigmatic observation that the same HLA sequence differentially affects RA risk through Mendelian inheritance vs. microchimeric cell acquisition.

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 CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness

2002 ◽  
Vol 196 (2) ◽  
pp. 237-246 ◽  
Author(s):  
Ciriaco A. Piccirillo ◽  
John J. Letterio ◽  
Angela M. Thornton ◽  
Rebecca S. McHugh ◽  
Mizuko Mamura ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Transforming Growth Factor ◽  
Cell Contact ◽  
Suppressor Function ◽  
Tgf Β1

CD4+CD25+ regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4+CD25−T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact–dependent and cytokine independent. The role of TGF-β1 in CD4+CD25+ suppressor function remains unclear. While most studies have failed to reverse suppression with anti–transforming growth factor (TGF)-β1 in vitro, one recent study has reported that CD4+CD25+ T cells express cell surface TGF-β1 and that suppression can be completely abrogated by high concentrations of anti–TGF-β suggesting that cell-associated TGF-β1 was the primary effector of CD4+CD25+-mediated suppression. Here, we have reevaluated the role of TGF-β1 in CD4+CD25+-mediated suppression. Neutralization of TGF-β1 with either monoclonal antibody (mAb) or soluble TGF-βRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4+CD25+ T cells. Responder T cells from Smad3−/− or dominant-negative TGF-β type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-β1–induced growth arrest, were as susceptible to CD4+CD25+-mediated suppression as T cells from wild-type mice. Furthermore, CD4+CD25+ T cells from neonatal TGF-β1−/− mice were as suppressive as CD4+CD25+ from TGF-β1+/+ mice. Collectively, these results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-β1.

Activated T cells complicate the identification of regulatory T cells in rheumatoid arthritis

2008 ◽  
Vol 251 (2) ◽  
pp. 109-115 ◽  
Author(s):  
Nicolaas E. Aerts ◽  
Evelyne J. Dombrecht ◽  
Didier G. Ebo ◽  
Chris H. Bridts ◽  
Wim J. Stevens ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Activated T Cells

scholarly journals Efficient Therapeutic Function and Mechanisms of Human Polyclonal CD8+CD103+Foxp3+ Regulatory T Cells on Collagen-Induced Arthritis in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Juan Sun ◽  
Yiming Yang ◽  
Xiaona Huo ◽  
Beibei Zhu ◽  
Zhenhua Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cells ◽  
Regulatory T Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Therapeutic Effects ◽  
Igg Antibody ◽  
Th1 Cell ◽  
Inflammatory Microenvironment

Objective. To investigate the potential therapeutic effect in a rheumatoid arthritis model of stable human CD8+ regulatory T cells (hCD8+Tregs) induced by TGF-β1 and rapamycin (RAPA) in vitro. Methods. Human CD8+T cells were isolated from human peripheral blood mononuclear cells and induced/expanded with TGF-β1 and RAPA along with anti-CD3/28 beads and IL-2 in vitro and harvested as hCD8+Tregs. The phenotypes, suppressive characteristics, and stability of the hCD8+Tregs in an inflammatory microenvironment were examined in vitro. Human CD8+Tregs were transfused into an acollagen-induced arthritis (CIA) mouse model, and their therapeutic effects and related mechanisms were investigated. Results. Human CD8+Tregs induced by TGF-β1/RAPA showed high expression of Foxp3 and CD103, exhibited vigorous suppression ability, and were stable in inflammatory microenvironments. In CIA mice, the clinical scores, levels of anti-collagen IgG antibody, and cartilage destruction were significantly reduced after adoptive transfusion with hCD8+Tregs. Moreover, hCD8+Treg treatment significantly reduced the number of Th17 cells, increased the number of CD4+IFN-γ+T cells, and produced self CD4+Foxp3+Tregs in vivo. In an in vitro cell coculture assay, hCD8+Tregs significantly inhibited mouse CD4+ effector T cell proliferation, induced mouse CD4+Foxp3+Treg and CD4+IFN-γ+Th1 cell production, reduced Th17 cell development, and downregulated CD80/86 expression on mature DCs (mDCs). Conclusion. TGF-β1/RAPA can induce hCD8+Tregs with stable suppressive characteristics, which could significantly alleviate the severity of CIA based on their stable suppressive ability in an inflammatory microenvironment and further influence the function of other downstream cell subtypes. Human CD8+Tregs might be a therapeutic strategy for rheumatoid arthritis.

scholarly journals The Ets-1 transcription factor controls the development and function of natural regulatory T cells

2010 ◽  
Vol 207 (10) ◽  
pp. 2113-2125 ◽  
Author(s):  
Enguerran Mouly ◽  
Karine Chemin ◽  
Hai Vu Nguyen ◽  
Martine Chopin ◽  
Laurent Mesnard ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Regulatory T Cells ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Regulatory Sequence ◽  
Activated T Cells ◽  
And Function

Regulatory T cells (T reg cells) constitute a population of CD4+ T cells that limits immune responses. The transcription factor Foxp3 is important for determining the development and function of T reg cells; however, the molecular mechanisms that trigger and maintain its expression remain incompletely understood. In this study, we show that mice deficient for the Ets-1 transcription factor (Ets-1−/−) developed T cell–mediated splenomegaly and systemic autoimmunity that can be blocked by functional wild-type T reg cells. Spleens of Ets-1−/− mice contained mostly activated T cells, including Th2-polarized CD4+ cells and had reduced percentages of T reg cells. Splenic and thymic Ets-1−/− T reg cells expressed low levels of Foxp3 and displayed the CD103 marker that characterizes antigen-experienced T reg cells. Thymic development of Ets-1−/− T reg cells appeared intrinsically altered as Foxp3-expressing cells differentiate poorly in mixed fetal liver reconstituted chimera and fetal thymic organ culture. Ets-1−/− T reg cells showed decreased in vitro suppression activity and did not protect Rag2−/− hosts from naive T cell–induced inflammatory bowel disease. Furthermore, in T reg cells, Ets-1 interacted with the Foxp3 intronic enhancer and was required for demethylation of this regulatory sequence. These data demonstrate that Ets-1 is required for the development of natural T reg cells and suggest a role for this transcription factor in the regulation of Foxp3 expression.

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