Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells

Science ◽  
2018 ◽  
Vol 362 (6417) ◽  
pp. 952-956 ◽  
Author(s):  
Stéphanie Liénart ◽  
Romain Merceron ◽  
Christophe Vanderaa ◽  
Fanny Lambert ◽  
Didier Colau ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Structural Basis ◽  
Amino Terminus ◽  
Latent Form ◽  
Close Proximity ◽  
Tgf Β1

Transforming growth factor–β1 (TGF-β1) is one of very few cytokines produced in a latent form, requiring activation to exert any of its vastly diverse effects on development, immunity, and cancer. Regulatory T cells (Tregs) suppress immune cells within close proximity by activating latent TGF-β1 presented by GARP (glycoprotein A repetitions predominant) to integrin αVβ8 on their surface. We solved the crystal structure of GARP:latent TGF-β1 bound to an antibody that stabilizes the complex and blocks release of active TGF-β1. This finding reveals how GARP exploits an unusual medley of interactions, including fold complementation by the amino terminus of TGF-β1, to chaperone and orient the cytokine for binding and activation by αVβ8. Thus, this work further elucidates the mechanism of antibody-mediated blockade of TGF-β1 activation and immunosuppression by Tregs.

CD28 disruption exacerbates inflammation in Tgf-β1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-β1

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4594-4601 ◽  
Author(s):  
Mizuko Mamura ◽  
WoonKyu Lee ◽  
Timothy J. Sullivan ◽  
Angelina Felici ◽  
Anastasia L. Sowers ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Cytotoxic T Lymphocyte ◽  
Tumor Necrosis Factor Receptor ◽  
Transforming Growth Factor Β1 ◽  
Autoimmune Inflammatory Disease ◽  
Lymph Node Cells ◽  
Tgf Β1

Abstract Tgf-β1-/- mice develop a progressive, lethal, inflammatory syndrome, but mechanisms leading to the spontaneous activation of Tgf-β1-/- T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-β1-/- mice, and we link this increase in severity to a reduction in the number of CD4+CD25+ regulatory T cells. CD4+CD25+ T cells develop normally in Tgf-β1-/- mice and display characteristic expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), αEβ7 integrin, and Foxp3. Adoptive transfer of Tgf-β1-/- splenocytes to Tgf-β1+/+/Rag2-/- mice induced an autoimmune inflammatory disease with features similar to those of the Tgf-β1-/- phenotype, and disease transfer was accelerated by the depletion of Tgf-β1-/- CD4+CD25+ T cells from donor splenocytes. Cotransfer of Tgf- β1-/- CD4+CD25+ T cells clearly attenuated disease in Rag2-/- recipients of CD25+-depleted Tgf-β1-/- spleen and lymph node cells, but suppression was incomplete when compared with Tgf-β1+/+ CD4+CD25+ T cells. These data demonstrate that CD4+CD25+ regulatory T cells develop in complete absence of endogenous transforming growth factor-β1 (TGF-β1) expression and that autocrine TGF-β1 expression is not essential for these cells to suppress inflammation in vivo. (Blood. 2004;103:4594-4601)

Leflunomide induces immunosuppression in collagen-induced arthritis rats by upregulating CD4+CD25+ regulatory T cells

2010 ◽  
Vol 88 (1) ◽  
pp. 45-53 ◽  
Author(s):  
Ting-Yu Wang ◽  
Jun Li ◽  
Chang-Yu Li ◽  
Yong Jin ◽  
Xiong-Wen Lü ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Con A ◽  
Collagen Induced Arthritis ◽  
Foxp3 Mrna ◽  
Tgf Β1

This study was to investigate the effect of leflunomide on the immunosuppressive CD4+CD25+ regulatory T cells (CD4+CD25+ Tregs) in collagen-induced arthritis (CIA) rats. CIA was induced by collagen type II in Wistar rats. Immunofluorescence flow cytometry and RT-PCR were used to determine the proportion of CD4+CD25+ Tregs and the expression of Foxp3 mRNA, respectively. Proliferation of T lymphocytes was assayed with MTT reagent, and the level of transforming growth factor β1 (TGF-β1) in the supernatant of concanavalin A (Con A)-induced T lymphocytes was determined by ELISA kit. Our investigations demonstrated that inhibition of arthritis by leflunomide was related to changes in CD4+CD25+ Tregs. In addition, A771726, which is the active metabolite of leflunomide, promoted the differentiation of spleen lymphocytes into CD4+CD25+ Tregs, increased antiinflammatory cytokine TGF-β1 secretion, and adjusted the activity of Con A-induced lymphocytes in vitro.

scholarly journals The Suppression of Th1 Response by Inducing TGF-β1 From Regulatory T Cells in Bovine Mycoplasmosis

2020 ◽  
Vol 7 ◽  
Author(s):  
Yamato Sajiki ◽  
Satoru Konnai ◽  
Shinya Goto ◽  
Tomohiro Okagawa ◽  
Kosuke Ohira ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Infected Cattle ◽  
Chronic Infections ◽  
Tgf Β1

Regulatory T cells (Tregs) regulate immune responses and maintain host immune homeostasis. Tregs contribute to the disease progression of several chronic infections by oversuppressing immune responses via the secretion of immunosuppressive cytokines, such as transforming growth factor (TGF)-β and interleukin-10. In the present study, we examined the association of Tregs with Mycoplasma bovis infection, in which immunosuppression is frequently observed. Compared with uninfected cattle, the percentage of Tregs, CD4+CD25highFoxp3+ T cells, was increased in M. bovis-infected cattle. Additionally, the plasma of M. bovis-infected cattle contained the high concentrations of TGF-β1, and M. bovis infection induced TGF-β1 production from bovine immune cells in in vitro cultures. Finally, we analyzed the immunosuppressive effects of TGF-β1 on bovine immune cells. Treatment with TGF-β1 significantly decreased the expression of CD69, an activation marker, in T cells, and Th1 cytokine production in vitro. These results suggest that the increase in Tregs and TGF-β1 secretion could be one of the immunosuppressive mechanisms and that lead to increased susceptibility to other infections in terms of exacerbation of disease during M. bovis infection.

scholarly journals Hepatocellular Carcinoma Cells Induce Regulatory T Cells and Lead to Poor Prognosis via Production of Transforming Growth Factor-β1

2016 ◽  
Vol 38 (1) ◽  
pp. 306-318 ◽  
Author(s):  
Yi Wang ◽  
Taotao Liu ◽  
Wenqing Tang ◽  
Bin Deng ◽  
Yanjie Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Poor Prognosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
In Vivo Experiments ◽  
Tgf Β1

Background/Aims: Regulatory T cells (Tregs) are associated with a poor prognosis in hepatocellular carcinoma (HCC). The purpose of the study was to explore the mechanisms of Tregs accumulation in HCC. Methods: We analyzed the frequency of Tregs in HCC by flow cytometry and immunohistochemistry. We also established a transforming growth factor (TGF)-β1-knockdown cell line by lentivirus-mediated RNA interference. Mouse CD4+CD25- T cells were cultured in supernatants from various cell lines. Results: HCC patients had a high frequency of Tregs, and high numbers of Tregs correlated with a poor prognosis. Liver cancer cells induced Treg production by secreting TGF-β1. In vivo experiments indicated that knockdown of TGF-β1 reduced the numbers of Tregs and metastatic nodules in mice. Conclusions: These results indicate that cancer-secreted TGF-β1 may increase Tregs, and TGF-β1 knockdown might impair immunosuppression in the tumor microenvironment by decrease Tregs.

scholarly journals Lysosomal-associated Transmembrane Protein 4B (LAPTM4B) Decreases Transforming Growth Factor β1 (TGF-β1) Production in Human Regulatory T Cells

2015 ◽  
Vol 290 (33) ◽  
pp. 20105-20116 ◽  
Author(s):  
Caroline Huygens ◽  
Stéphanie Liénart ◽  
Olivier Dedobbeleer ◽  
Julie Stockis ◽  
Emilie Gauthy ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Transforming Growth Factor ◽  
Transmembrane Protein ◽  
Transforming Growth Factor Β1 ◽  
Tgf Β1

scholarly journals Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Jochen Michael Rudolph ◽  
Karina Guttek ◽  
Gabriele Weitz ◽  
Clara Antonia Meinke ◽  
Stefanie Kliche ◽  
...  
Keyword(s):  
T Cells ◽  
Knockout Mice ◽  
Transforming Growth Factor ◽  
Severe Disease ◽  
Transforming Growth Factor Β1 ◽  
Regulatory Function ◽  
Platelet Factor ◽  
Tgf Β1

ABSTRACT The adhesion and degranulation-promoting adapter protein (ADAP) is expressed in T cells, NK cells, myeloid cells, and platelets. The involvement of ADAP in the regulation of receptor-mediated inside-out signaling leading to integrin activation is well characterized, especially in T cells and in platelets. Due to the fact that animal studies using conventional knockout mice are limited by the overlapping effects of the different ADAP-expressing cells, we generated conditional ADAP knockout mice (ADAPfl/fl PF4-Cretg) (PF4, platelet factor 4). We observed that loss of ADAP restricted to the megakaryocytic lineage has no impact on other hematopoietic cells even under stimulation conditions. ADAPfl/fl PF4-Cretg mice showed thrombocytopenia in combination with reduced plasma levels of PF4 and transforming growth factor β1 (TGF-β1). In vitro, platelets from these mice revealed reduced P-selectin expression, lower levels of TGF-β1 release, diminished integrin αIIbβ3 activation, and decreased fibrinogen binding after stimulation with podoplanin, the ligand of C-type lectin-like receptor 2 (CLEC-2). Furthermore, loss of ADAP was associated with impaired CLEC-2-mediated activation of phospholipase Cγ2 (PLCγ2) and extracellular signal-regulated kinase 1/2 (ERK1/2). Induction of experimental autoimmune encephalomyelitis (EAE) in mice lacking ADAP expression in platelets caused a more severe disease. In vivo administration of TGF-β1 early after T cell transfer reduced EAE severity in mice with loss of ADAP restricted to platelets. Our results reveal a regulatory function of ADAP in platelets in vitro and during autoimmune disease EAE in vivo.

Influences of High-Dose Dexamethasone on Regulatory T Cells, Transforming Growth Factor-β1 and Interleukin-10 of Patients with Chronic ITP.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3920-3920
Author(s):  
Yun Ling ◽  
Xiangshan Cao ◽  
Ziqiang Yu ◽  
Changgeng Ruan
Keyword(s):  
T Cells ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Treg Cells ◽  
Transforming Growth Factor Β1 ◽  
High Dose ◽  
Chronic Itp ◽  
High Dose Dexamethasone ◽  
Significant Difference ◽  
Tgf Β1

Abstract Immune thrombocytopenic purpura (ITP) is an autoimmune disorder and high-dose dexamethasone (HD-DXM) has been used as a first-line therapy for patients with ITP. However, little is known about the role of CD4+CD25 + regulatory T (Treg) cells, interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) in the pathogenesis of chronic ITP and the effects of HD-DXM on them contained Treg cells, IL-10 and TGF-β1. In this study, we investigated the expressions of Treg cells, IL-10 and TGF-β1 in 26 untreated adult patients with chronic ITP. All patients had thrombocytopenia (platelet count <50 × 109/L) for more than 6 months. We also observed short time changes of Treg cells, IL-10 and TGF-β1 after treatment with HD-DXM in these patients. The results showed that a good initial response to HD-DXM occurred in 24 of the 26 patients with chronic ITP (92.3%): the mean platelet count was (84.9±30.4)×109/L [range, (20∼150) ×109/L] one week after the initiation of treatment. The proportion of CD4+CD25+ T cells in the peripheral blood of patients with chronic ITP was significantly higher than that in normal controls(P<0.001); there was no significant difference in the percentage of CD4+CD25high T cells between patients and controls ( P=0.317); but the number of CD4+ FOXP3+ T cells in patients was significantly lower than that in controls (P<0.001). After 4-days treatment with HD-DXM, the numbers of CD4+ CD25+ T cells (P<0.001), CD4+CD25high T cells ( P<0.001), and CD4+FOXP3+ T cells ( P<0.001) in patients were all significantly increased. In the serum of chronic ITP patients, the expression level of TGF-β1 was lower than that of healthy controls (P<0.0001) and HD-DXM could significantly increase it; there was no significant difference in the expression level of IL-10 between patients and controls ( P>0.05) and there was no remarkable change of IL-10 in patients after HD-DXM treatment (P>0.05). The mRNA levels of Foxp3 and TGF-β1 gene in patients were lower than those of controls (P<0.05 and P<0.05); HD-DXM administration significantly increased the expressions of Foxp3 and TGF-β1 gene(P<0.05 and P<0.0001), which were even higher than those of controls(P<0.05 and P<0.05); There was a positive correlation between the Foxp3 mRNA expression and TGF-β1 after treatment with HD-DXM (r =0.403, P=0.041). These results suggest that Foxp3 and TGF-β1 gene are deficient in chronic ITP and the immunosuppressive therapy of glucocorticoids could improve the expression levels of these genes.

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.

The Link Between Seminal Cytokine Interleukin 18, Female Circulating Regulatory T Cells, and IVF/ICSI Success

2018 ◽  
Vol 26 (8) ◽  
pp. 1034-1044 ◽  
Author(s):  
Marina Nikolaeva ◽  
Alina Babayan ◽  
Elena Stepanova ◽  
Alla Arefieva ◽  
Tatiana Dontsova ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Peripheral Blood ◽  
Transforming Growth Factor ◽  
Embryo Implantation ◽  
Female Reproductive Tract ◽  
Vitro Fertilization ◽  
Treg Frequency ◽  
Tgf Β1

Seminal plasma (SP) is thought to be a crucial factor which affects the expansion of regulatory T cells (Tregs) in female reproductive tract during embryo implantation. We propose that seminal transforming growth factor (TGF) β1 is responsible for local accumulation of circulating Tregs, which manifests as changes in Treg frequency in peripheral blood, whereas seminal interleukin (IL) 18 interferes with TGF-β1-dependent cellular reactions. The purpose of the present study is to determine whether the frequency of circulating Tregs is associated with the levels of seminal cytokines and pregnancy establishment in women exposed to partner’s SP during in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycle. Twenty-nine women were exposed to SP via timed intercourse before the day of ovum pickup (day-OPU) and also subjected to intravaginal SP application just after OPU. Measurements of seminal TGF-β1 and IL-18 were made by FlowCytomix technology. The percentage of CD4+CD25+CD127low+/ – Tregs among total circulating CD4+ T cells was determined by flow cytometry and the difference between Treg values on the day of embryo transfer and day-OPU was calculated. The percentage of Tregs on the day-OPU, identified as a predictive factor of clinical pregnancy after IVF/ICSI, showed a positive correlation with IL-18 concentration and content of this cytokine per ejaculate ( P < .001 and P < .004, respectively) and negative correlation with the TGF-β1/IL-18 ratio ( P < .014).These findings indicate that the adverse effect of seminal IL-18 excess on implantation may be realized by the prevention of postcoital TGF-β1-related migration of circulating Tregs, which clearly manifests as elevated level of Treg frequency in peripheral blood.

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